2′-chloroacetylenyl substituted nucleoside derivatives

ABSTRACT

The present invention relates to 2′-chloroacetylenyl-substituted nucleoside derivatives of the general formula (I): 
     
       
         
         
             
             
         
       
     
     As well as pharmaceutical compositions comprising such compounds and methods to treat or prevent an HIV infection, HBV infection, HCV infection or abnormal cellular proliferation, comprising administering said compounds or compositions. In addition, the present invention includes processes for the preparation of such compounds, and the related β-D and β-L-nucleoside derivatives.

RELATED APPLICATION(S)

This application claims the benefit of U.S. Provisional Application No.61/538,312, filed on Sep. 23, 2011. The entire teachings of the aboveapplication(s) are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates generally to compounds and pharmaceuticalcompositions useful as antiviral and antiproliferative agents.Specifically, the present invention relates to nucleoside derivativeswith 2′-chloroacetylenyl substitution and methods for their preparationand use.

BACKGROUND OF THE INVENTION

Synthetic nucleosides such as 5-iodouracil and 5-fluorouracil have beenused for the treatment of cancer for many years. Since the 1980's,synthetic nucleosides have also been a focus of interest for thetreatment of HIV and hepatitis.

In 1981, acquired immune deficiency syndrome (AIDS) was identified as adisease that severely compromises the human immune system and thatalmost without exception leads to death. In 1983, the etiological causeof AIDS was determined to be the human immunodeficiency virus (HIV). In1985, it was reported that the synthetic nucleoside3′-azido-3′-deoxythymidine (AZT) inhibits the replication of humanimmunodeficiency virus. Since then, a number of other syntheticnucleosides, including 2′,3′-dideoxyinosine (DDI), 2′,3′-dideoxycytidine(DDC), and 2′,3′-dideoxy-2′,3′-didehydrothymidine (D4T), have beenproven to be effective against HIV. After cellular phosphorylation tothe 5′-triphosphate by cellular kinases, these synthetic nucleosides areincorporated into a growing strand of viral DNA, causing chaintermination due to the absence of the 3′-hydroxyl group. They can alsoinhibit the viral enzyme reverse transcriptase.

The success of various synthetic nucleosides in inhibiting thereplication of HIV in vivo or in vitro has led a number of researchersto design and test nucleosides that substitute a heteroatom for thecarbon atom at the 3′-position of the nucleoside. European PatentPublication No. 0,337,713 and U.S. Pat. No. 5,041,449, assigned toBioChem Pharma, Inc., disclose2-substituted-4-substituted-1,3-dioxolanes that exhibit antiviralactivity. U.S. Pat. No. 5,047,407 and European Patent Publication No.0,382,526, also assigned to BioChem Pharma, Inc., disclose that a numberof 2-substituted-5-substituted-1,3-oxathiolane nucleosides haveantiviral activity, and specifically report that2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (referred to below asBCH-189) has approximately the same activity against HIV as AZT, withlittle toxicity.

It has also been disclosed thatcis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (“FTC”) haspotent HIV activity. Schinazi, et al., “Selective Inhibition of HumanImmunodeficiency viruses by Racemates and Enantiomers ofcis-5-Fluoro-1-[2-(Hydroxymethyl)-1,3-Oxathiolane-5-yl]-Cytosine”Antimicrobial Agents and Chemotherapy, November 1992, 2423-2431. Seealso U.S. Pat. Nos. 5,210,085; 5,814,639; and 5,914,331.

Another virus that causes a serious human health problem is thehepatitis B virus (referred to below as “HBV”). HBV is second only totobacco as a cause of human cancer. The mechanism by which HBV inducescancer is unknown. It is postulated that it may directly trigger tumordevelopment, or indirectly trigger tumor development through chronicinflammation, cirrhosis, and cell regeneration associated with theinfection.

After a two to six month incubation period in which the host is unawareof the infection, HBV infection can lead to acute hepatitis and liverdamage, that causes abdominal pain, jaundice, and elevated blood levelsof certain enzymes. HBV can cause fulminant hepatitis, a rapidlyprogressive, often fatal form of the disease in which massive sectionsof the liver are destroyed.

Patients typically recover from acute hepatitis. In some patients,however, high levels of viral antigen persist in the blood for anextended or indefinite period, causing a chronic infection. Chronicinfections can lead to chronic persistent hepatitis. Patients infectedwith chronic persistent HBV are most common in developing countries. Bymid-1991, there were approximately 225 million chronic carriers of HBVin Asia alone, and worldwide, almost 300 million carriers. Chronicpersistent hepatitis can cause fatigue, cirrhosis of the liver, andhepatocellular carcinoma, a primary liver cancer.

In western industrialized countries, high risk groups for HBV infectioninclude those in contact with HBV carriers or their blood samples. Theepidemiology of HBV is very similar to that of acquired immunedeficiency syndrome, which accounts for why HBV infection is commonamong patients with AIDS or AIDS related complex. However, HBV is morecontagious than HIV.

Both FTC and 3TC exhibit activity against HBV. Furman, et al., “TheAnti-Hepatitis B Virus Activities, Cytotoxicities, and Anabolic Profilesof the (−) and (+) Enantiomers ofcis-5-Fluoro-1-[2-(Hydroxymethyl)-1,3-oxathiolane-5-yl]-Cytosine”Antimicrobial Agents and Chemotherapy, December 1992, pp. 2686-2692; andCheng, et al., Journal of Biological Chemistry, Volume 267(20), pp.13938-13942 (1992). Other compounds that exhibit activity against HBV inhumans include Clevudine or CLV (L-FMAU) (Pharmasset, Inc. under licensefrom The University of Georgia Research Foundation and Yale University),and L-dT and L-dC (Idenix Pharmaceuticals, Inc.).

HCV is the major causative agent for post-transfusion and for sporadicnon A, non B hepatitis (Alter, H. J. (1990) J. Gastro. Hepatol. 1:78-94;Dienstag, J. L. (1983) Gastro 85:439-462). Despite improved screening,HCV still accounts for at least 25% of the acute viral hepatitis in manycountries (Alter, H. J. (1990) supra; Dienstag, J. L. (1983) supra;Alter M. J. et al. (1990a) J.A.M.A. 264:2231-2235; Alter M. J. et at(1992) N. Engl. J. Med. 327:1899-1905; Alter, M. J. et al. (1990b) N.Engl. J. Med. 321:1494-1500). Infection by HCV is insidious in a highproportion of chronically infected (and infectious) carriers who may notexperience clinical symptoms for many years. The high rate ofprogression of acute infection to chronic infection (70-100%) and liverdisease (>50%), its world-wide distribution and lack of a vaccine makeHCV a significant cause of morbidity and mortality. Currently, there arethree types of interferon and a combination of interferon and ribavirinused to treat hepatitis C. Selection of patients for treatment may bedetermined by biochemical, virologic, and when necessary, liver biopsyfindings, rather than presence or absence of symptoms.

Interferon is given by injection, and may have a number of side effectsincluding flu-like symptoms including headaches, fever, fatigue, loss ofappetite, nausea, vomiting, depression and thinning of hair. It may alsointerfere with the production of white blood cells and platelets bydepressing the bone marrow. Periodic blood tests are required to monitorblood cells and platelets. Ribavirin can cause sudden, severe anemia,and birth defects so women should avoid pregnancy while taking it andfor 6 months following treatment. The severity and type of side effectsdiffer for each individual. Treatment of children with HCV is notcurrently approved but is under investigation. While 50-60% of patientsrespond to treatment initially, lasting clearance of the virus occurs inonly about 10-40% of patients. Treatment may be prolonged and given asecond time to those who relapse after initial treatment. Re-treatmentwith bioengineered consensus interferon alone results in elimination ofthe virus in 58% of patients treated for one year. Side effects occurbut the medication is usually well tolerated. Combined therapy(interferon and ribavirin) shows elimination of the virus in 47% after 6months of therapy. Side effects from both drugs may be prominent.

A tumor is an unregulated, disorganized proliferation of cell growth. Atumor is malignant, or cancerous, if it has the properties ofinvasiveness and metastasis. Invasiveness refers to the tendency of atumor to enter surrounding tissue, breaking through the basal laminasthat define the boundaries of the tissues, thereby often entering thebody's circulatory system. Metastasis refers to the tendency of a tumorto migrate to other areas of the body and establish areas ofproliferation away from the site of initial appearance.

Cancer is now the second leading cause of death in the United States.Over 8,000,000 persons in the United States have been diagnosed withcancer, with 1,208,000 new diagnoses expected in 1994. Over 500,000people die annually from the disease in this country.

Cancer is not fully understood on the molecular level. It is known thatexposure of a cell to a carcinogen such as certain viruses, certainchemicals, or radiation, leads to DNA alteration that inactivates a“suppressive” gene or activates an “oncogene.” Suppressive genes aregrowth regulatory genes, which upon mutation, can no longer control cellgrowth. Oncogenes are initially normal genes (called prooncongenes) thatby mutation or altered context of expression become transforming genes.The products of transforming genes cause inappropriate cell growth. Morethan twenty different normal cellular genes can become oncongenes bygenetic alteration. Transformed cells differ from normal cells in manyways, including cell morphology, cell-to-cell interactions, membranecontent, cytoskeletal structure, protein secretion, gene expression andmortality (transformed cells can grow indefinitely).

All of the various cell types of the body can be transformed into benignor malignant tumor cells. The most frequent tumor site is lung, followedby colorectal, breast, prostate, bladder, pancreas and then ovary. Otherprevalent types of cancer include leukemia, central nervous systemcancers, including brain cancer, melanoma, lymphoma, erythroleukemia,uterine cancer, and head and neck cancer.

Cancer is now primarily treated with one or a combination of three meansof therapies: surgery, radiation and chemotherapy. Surgery involves thebulk removal of diseased tissue. While surgery is sometimes effective inremoving tumors located at certain sites, for example, in the breast,colon and skin, it cannot be used in the treatment of tumors located inother areas, such as the backbone, or in the treatment of disseminatedneoplastic conditions such as leukemia.

Chemotherapy involves the disruption of cell replication or cellmetabolism. It is used most often in the treatment of leukemia, as wellas breast, lung, and testicular cancer.

There are five major classes of chemotherapeutic agents currently in usefor the treatment of cancer: natural products and their derivatives;anthacyclines; alkylating agents; antiproliferatives (also calledantimetabolites); and hormonal agents. Chemotherapeutic agents are oftenreferred to as antineoplastic agents.

The alkylating agents are believed to act by alkylating andcross-linking guanine and possibly other bases in DNA, arresting celldivision. Typical alkylating agents include nitrogen mustards,ethyleneimine compounds, alkyl sulfates, cisplatin and variousnitrosoureas. A disadvantage with these compounds is that they not onlyattack malignant cells, but also other cells which are naturallydividing, such as those of bone marrow, skin, gastrointestinal mucosa,and fetal tissue.

Antimetabolites are typically reversible or irreversible enzymeinhibitors, or compounds that otherwise interfere with the replication,translation or transcription of nucleic acids.

Several synthetic nucleosides have been identified that exhibitanticancer activity. A well known nucleoside derivative with stronganticancer activity is 5-fluorouracil. 5-Fluorouracil has been usedclinically in the treatment of malignant tumors, including, for example,carcinomas, sarcomas, skin cancer, cancer of the digestive organs, andbreast cancer. 5-Fluorouracil, however, causes serious adverse reactionssuch as nausea, alopecia, diarrhea, stomatitis, leukocyticthrombocytopenia, anorexia, pigmentation and edema. Derivatives of5-fluorouracil with anti-cancer activity have been described in U.S.Pat. No. 4,336,381, and in Japanese patent publication Nos. 50-50383,50-50384, 50-64281, 51-146482, and 53-84981.

U.S. Pat. No. 4,000,137 discloses that the peroxidate oxidation productof inosine, adenosine or cytidine with methanol or ethanol has activityagainst lymphocytic leukemia.

Cytosine arabinoside (also referred to as Cytarabin, araC, and Cytosar)is a nucleoside analog of deoxycytidine that was first synthesized in1950 and introduced into clinical medicine in 1963. It is currently animportant drug in the treatment of acute myeloid leukemia. It is alsoactive against acute lymphocytic leukemia, and to a lesser extent, isuseful in chronic myelocytic leukemia and non-Hodgkin's lymphoma. Theprimary action of araC is inhibition of nuclear DNA synthesis.Handschumacher, R. and Cheng, Y., “Purine and PyrimidineAntimetabolites” Cancer Medicine, Chapter XV-I, 3rd Edition, Edited byJ. Holland, et al., Lea and Febigol, publishers.

5-Azacytidine is a cytidine analog that is primarily used in thetreatment of acute myelocytic leukemia and myelodysplastic syndrome.

2-Fluoroadenosine-5′-phosphate (Fludara, also referred to as FaraA) isone of the most active agents in the treatment of chronic lymphocyticleukemia. The compound acts by inhibiting DNA synthesis. Treatment ofcells with F-araA is associated with the accumulation of cells at theG1/S phase boundary and in S phase; thus, it is a cell cycle Sphase-specific drug. Incorporation of the active metabolite, F-araATP,retards DNA chain elongation. F-araA is also a potent inhibitor ofribonucleotide reductase, the key enzyme responsible for the formationof dATP.

2-Chlorodeoxyadenosine is useful in the treatment of low grade B-cellneoplasms such as chronic lymphocytic leukemia, non-Hodgkins' lymphoma,and hairy-cell leukemia.

In light of the fact that acquired immune deficiency syndrome,AIDS-related complex, hepatitis B virus and hepatitis C virus havereached epidemic levels worldwide, and have tragic effects on theinfected patient, there remains a strong need to provide new effectivepharmaceutical agents to treat these diseases that have low toxicity tothe host. Further, there is a need to provide new antiproliferativeagents.

Therefore, it is an object of the present invention to provide a methodand composition for the treatment of human patients or other hostanimals infected with HIV.

It is another object of the present invention to provide a method andcomposition for the treatment of human patients infected with hepatitisB or C.

It is a further object of the present invention to provide newantiproliferative agents.

It is still another object of the present invention to provide a newprocess for the preparation of 2′-chloroacetylenyl-substitutednucleoside derivatives of the present invention.

SUMMARY OF THE INVENTION

The present invention includes β-D and β-L-nucleoside derivatives,pharmaceutical compositions comprising such compounds, as well asmethods to treat or prevent an HIV infection, HBV infection, HCVinfection or abnormal cellular proliferation, comprising administeringsaid compounds or compositions. In addition, the present inventionincludes processes for the preparation of such compounds, and therelated β-D and β-L-nucleoside derivatives.

The compounds of the invention are 2′-chloroacetylenyl-substitutednucleoside derivatives of the general formula (I):

or the β-L enantiomer thereof, or a pharmaceutically acceptable salt,ester, stereoisomer, tautomer, solvate, prodrug, or combination thereof,wherein:R₁ is selected from the group consisting of:

-   -   1) hydrogen;    -   2) —CN;    -   3) halogen;    -   4) —N₃; and    -   5) Substituted or unsubstituted —C₁-C₈ alkyl;        R₂ and R_(4a) are independently selected from the group        consisting of:    -   1) halogen;    -   2) —CN;    -   3) —N₃; and    -   4) OR₆; where R₆ is selected from the group consisting of:        hydrogen, hydroxy protecting group, —C(O)R₇, —C(O)OR₇, and        —C(O)NR_(8a)R_(8b); wherein R₇ is selected from the group        consisting of: substituted or unsubstituted —C₁-C₈ alkyl,        substituted or unsubstituted —C₂-C₈ alkenyl, substituted or        unsubstituted —C₂-C₈ alkynyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, and substituted or        unsubstituted heterocyclic; R_(8a) and R_(8b) are each        independently selected from the group consisting of: hydrogen        and R₇; or alternatively R_(8a) and R_(8b) taken together with        the nitrogen atom to which they are attached form a heterocyclic        ring;        R₃ is R₆; or alternatively R₂ is —OR₆ and R₃ and R₆ together        form a group selected from: —C(Me)₂-, —C(CH₂)₄—, —CH(Ph)—,        —CH(OMe)— and —P(O)(OH)—.        B is selected from the group consisting of: substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl, and        substituted or unsubstituted heterocyclic; preferably a        heterocycle containing at least one nitrogen atom.        R_(5a) and R_(5b) are independently selected from the group        consisting of:    -   1) hydrogen;    -   2) substituted or unsubstituted —C₁-C₈ alkyl;    -   3) substituted or unsubstituted —C₂-C₈ alkenyl;    -   4) substituted or unsubstituted —C₂-C₈ alkynyl; and    -   5) or R_(5a) and R_(5b) are taken together with the carbon atoms        to which they are attached to form a group selected from —C₃-C₈        cycloalkyl, —C₃-C₈ cycloalkenyl, or —C₃-C₈ cycloalkynyl.        R₅ is selected from the group consisting of:    -   1) hydrogen;    -   2) R₆;    -   3) —P(O)(OR_(7a))(OR_(7b)); wherein R_(7a) and R_(7b) are each        independently selected from the group consisting of a)        hydrogen; b) unsubstituted or substituted —C₁-C₈ alkyl;    -   4) —P(O)(OR_(7a))—O—P(O)(OR_(7b))(OR_(7c)); wherein R_(7a) and        R_(7b) are previously defined; R_(7c) is selected from the group        consisting of a) hydrogen; b) unsubstituted or substituted        —C₁-C₈ alkyl;    -   5) —P(O)(OR_(7a))—O—P(O)(OR_(7b))—O—P(O)(OR_(7c))(OR_(7d));        wherein R_(7a), R_(7b) and R_(7c) are previously defined; R_(7d)        is selected from the group consisting of a) hydrogen; b)        unsubstituted or substituted —C₁-C₈ alkyl;    -   6)

where X is O or S; R₉ is R₇ wherein R₇ is previously defined; R₁₀, R₁₁and R₁₂ are each independently selected from the group consisting of: a)hydrogen; and b) unsubstituted or substituted —C₁-C₈ alkyl; or R₁₁ ishydrogen, R₁₂ and R₁₀ taken together with the nitrogen which R₁₀ isattached to form a heterocyclic ring; or R₁₁ and R₁₂ taken together withthe carbon which they are attached form a ring, preferably a carbocyclicor heterocyclic ring, and more preferably a cycloalkyl orcycloheteroalkyl ring; R₁₃ is hydrogen or R₇, wherein R₇ is previouslydefined; and

-   -   7)

where X is O or S; n is 1-4; R_(8a) and R_(8b) are as previouslydefined; R₁₄ is hydrogen or —(CO)—R₇, wherein R₇ is as previouslydefined.Or, R₅ and R₃ are taken together to form

where X is O or S; and R₆ is as previously defined.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor combination of compounds of the present invention, or apharmaceutically acceptable salt form, prodrug, salt of a prodrug,stereoisomer, tautomer, solvate, or combination thereof, in combinationwith a pharmaceutically acceptable carrier or excipient.

In yet another embodiment, the present invention provides a method ofinhibiting the replication of an RNA or DNA containing virus comprisingcontacting said virus with a therapeutically effective amount of acompound or a combination of compounds of the present invention, or apharmaceutically acceptable salt, prodrug, salt of a pro drug,stereoisomer, tautomer, solvate, or combination thereof. Particularly,this invention is directed to methods of inhibiting the replication ofHIV, HBV and HCV.

In still another embodiment, the present invention provides a method oftreating or preventing infection caused by an RNA or DNA-containingvirus comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound or combination ofcompounds of the present invention, or a pharmaceutically acceptablesalt form, prodrug, salt of a prodrug, stereoisomer, or tautomer,solvate, or combination thereof. Particularly, this invention isdirected to methods of treating or preventing infection caused by HIV,HBV and HCV.

Yet another embodiment of the present invention provides the use of acompound or combination of compounds of the present invention, or atherapeutically acceptable salt form, prodrug, salt of a prodrug,stereoisomer or tautomer, solvate, or combination thereof, as definedhereinafter, in the preparation of a medicament for the treatment orprevention of infection caused by RNA or DNA-containing virus,specifically HIV, HBV and HCV.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment of the present invention is a compound of Formula(I) as illustrated above, or a pharmaceutically acceptable salt, esteror prodrug thereof.

In a particular embodiment of the present invention is a β-D2′-chloroacetylenyl substituted nucleoside derivatives represented byformula (II), or its β-L enantiomer, or pharmaceutically acceptable saltor prodrug thereof:

wherein R₁, R₂, R_(4a), R_(5a), R_(5b), R₃, B are as previously defined.

Illustrative structures of formula (II) can be represented, but notlimited, by formula (II-1˜II-25) and the β-L enantiomers thereof:

wherein B is as previously defined;

In another particular embodiment of the present invention is a β-D2′-chloroacetylenyl-substituted nucleoside diester derivativesrepresented by formula (III), or its β-L enantiomer, or pharmaceuticallyacceptable salt or prodrug thereof:

wherein R₁, R₂, R_(5a), R_(5b), R₇, and B are as previously defined.

In another particular embodiment of the present invention is a β-D2′-chloroacetylenyl-substituted nucleoside phosphonamidate derivativerepresented by formula (IV), or its β-L enantiomer, or apharmaceutically acceptable salt or prodrug thereof:

wherein R₁, R₂, R_(5a), R_(5b), R₃, R₉, R₁₀, R₁₁, R₁₂, R₁₃, and B are aspreviously defined. X is O or S. Illustrative structures of formula (IV)can be represented, but not limited, by formula (IV-1˜IV-12):

wherein R₁, R₂, R_(5a), R_(5b), and B are as previously defined.

In another particular embodiment of the present invention is a β-D2′-chloroacetylenyl-substituted nucleoside phosphate derivativerepresented by formula (V), or its β-L enantiomer, or a pharmaceuticallyacceptable salt or prodrug thereof:

wherein R₁, R₂, R_(5a), R_(5b), R₃, R_(8a), R_(8b), R₁₄, and B are aspreviously defined. X is O or S. n is 1˜4.

In still another particular embodiment of the present invention is a β-D2′-chloroacetylenyl-substituted nucleoside phosphate derivativerepresented by formula (VI), or its β-L enantiomer, or apharmaceutically acceptable salt or prodrug thereof:

wherein R₁, R₂, R_(5a), R_(5b), R₆, and B are as previously defined. Xis O or S.

In yet another particular embodiment of the present invention is a β-D2′-chloroacetylenyl-substituted nucleoside derivative represented byformulas (I) to (VI), or the β-L enantiomer, or a pharmaceuticallyacceptable salt or prodrug thereof, with B at each occurrence is anoptionally substituted aryl, heteroaryl, or heterocyclic; preferably aheterocycle moiety containing at least one nitrogen, most preferably apyrimidinyl, purinyl group or the like of the general formula of (B1)and (B2):

wherein:

-   -   Y is selected from a group consisting of: O, S, NR_(8a),        NC(O)R₇, NC(O)OR₇ and NC(O)NR_(8a)R_(8b);    -   T, U, V and W are independently N or CR₁₈; wherein R₁₈ is        selected from a group consisting of: hydrogen, halogen, —CN,        —C(O)R₇, —C(O)NR_(8a)R_(8b), —NO₂, —N₃, —OR₇, —SR₇,        —NR_(8a)R_(8b), —OC(O)R₇, —OC(O)OR₇, —NHC(O)R₇, —NHC(O)OR₇ and        —NHC(O)NR_(8a)R_(8b), substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, substituted or        unsubstituted heterocyclic, substituted or unsubstituted —C₁-C₈        alkyl, substituted or unsubstituted —C₂-C₈ alkenyl, substituted        or unsubstituted —C₂-C₈ alkenyl;    -   R¹⁵, R¹⁶ and R¹⁷ at each occurrence are independently selected        from a group consisting of: hydrogen, halogen, —CN, —C(O)R₇,        —C(O)NR_(8a)R_(8b), —NO₂, —N₃, —OR₇, —SR₇, —NR_(8a)R_(8b),        —OC(O)R₇, —OC(O)OR₇, —NHC(O)R₇, —NHC(O)OR₇ and        —NHC(O)NR_(8a)R_(8b), substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, substituted or        unsubstituted heterocyclic, substituted or unsubstituted —C₁-C₈        alkyl, substituted or unsubstituted —C₂-C₈ alkenyl, substituted        or unsubstituted —C₂-C₈ alkynyl.        Illustrative structures of B are represented by formula        (B1a˜B1r), (B2a˜B2o), and (B3a˜B3j):

wherein R_(8a), R₁₈, R₁₄, R¹⁵, R¹⁶ and R¹⁷ are as previously defined.

Representative compounds of the invention include, but are not limitedto, the following compounds illustrated in Table 1 to Table 5.

Table 1 sets forth compounds of Formula (II-1) wherein R₂, R_(4a),R_(5a), R_(5b), and B are delineated for each example in Table 1.

TABLE 1 (II-1)

Example # R_(5a) R_(5b) R_(4a) R₂ B 1 H H H OH

2 H H H F

3 H H N₃ OH

4 H H N₃ F

5 H Me H OH

6 H Me H F

7 Me H H OH

8 Me H H F

9 H H H OH

10 H H H F

11 H H N₃ OH

12 H H N₃ F

13 H Me H OH

14 H Me H F

15 Me H H OH

16 Me H H F

17 H H H OH

18 H H H F

19 H H N₃ OH

20 H H N₃ F

21 H Me H OH

22 H Me H F

23 Me H H OH

24 Me H H F

25 H H H OH

26 H H H F

27 H H N₃ OH

28 H H N₃ F

29 H Me H OH

30 H Me H F

31 Me H H OH

32 Me H H F

33 H H H OH

34 H H H F

35 H H N₃ OH

36 H H N₃ F

37 H Me H OH

38 H Me H F

39 Me H H OH

40 Me H H F

41 H H H OH

42 H H H F

43 H H N₃ OH

44 H H N₃ F

45 H Me H OH

46 H Me H F

47 Me H H OH

48 Me H H F

49 H H H OH

50 H H H F

51 H H N₃ OH

52 H H N₃ F

53 H Me H OH

54 H Me H F

55 Me H H OH

56 Me H H F

57 H H H OH

58 H H H F

59 H H N₃ OH

60 H H N₃ F

61 H Me H OH

62 H Me H F

63 Me H H OH

64 Me H H F

65 H H H OH

66 H H H F

67 H H N₃ OH

68 H H N₃ F

69 H Me H OH

70 H Me H F

71 Me H H OH

72 Me H H F

73 H H H OH

74 H H H F

75 H H N₃ OH

76 H H N₃ F

77 H Me H OH

78 H Me H F

79 Me H H OH

80 Me H H F

Table 2 sets forth compounds of Formula (III-1) wherein R₂, R₇, R_(5a),R_(5b), and B are delineated for each example in Table 2.

TABLE 2 (III-1)

Example # R_(5a) R_(5b) R₂ R₇ B 81 H H OH i-Pr

82 H H F i-Pr

83 H Me OH i-Pr

84 H Me F i-Pr

85 Me H OH i-Pr

86 Me H F i-Pr

87 H H OH i-Pr

88 H H F i-Pr

89 H Me OH i-Pr

90 H Me F i-Pr

91 Me H OH i-Pr

92 Me H F i-Pr

93 H H OH i-Pr

94 H H F i-Pr

95 H Me OH i-Pr

96 H Me F i-Pr

97 Me H OH i-Pr

98 Me H F i-Pr

99 H H OH i-Pr

100 H H F i-Pr

101 H Me OH i-Pr

101a H Me F i-Pr

102 Me H OH i-Pr

103 Me H F i-Pr

104 H H OH i-Pr

105 H H F i-Pr

106 H Me OH i-Pr

107 H Me F i-Pr

108 Me H OH i-Pr

109 Me H F i-Pr

110 H H OH i-Pr

111 H H F i-Pr

112 H Me OH i-Pr

113 H Me F i-Pr

114 Me H OH i-Pr

115 Me H F i-Pr

116 H H OH i-Pr

117 H H F i-Pr

118 H Me OH i-Pr

119 H Me F i-Pr

120 Me H OH i-Pr

121 Me H F i-Pr

122 H H OH i-Pr

123 H H F i-Pr

124 H Me OH i-Pr

125 H Me F i-Pr

126 Me H OH i-Pr

127 Me H F i-Pr

128 H H OH i-Pr

129 H H F i-Pr

130 H Me OH i-Pr

131 H Me F i-Pr

132 Me H OH i-Pr

133 Me H F i-Pr

134 H H OH i-Pr

135 H H F i-Pr

136 H Me OH i-Pr

137 H Me F i-Pr

138 Me H OH i-Pr

139 Me H F i-Pr

140 H H OH Et

141 H H F Et

142 H Me OH Et

143 H Me F Et

144 Me H OH Et

145 Me H F Et

146 H H OH Et

147 H H F Et

148 H Me OH Et

149 H Me F Et

150 Me H OH Et

151 Me H F Et

152 H H OH Et

153 H H F Et

154 H Me OH Et

155 H Me F Et

156 Me H OH Et

157 Me H F Et

158 H H OH Et

159 H H F Et

160 H Me OH Et

161 H Me F Et

162 Me H OH Et

163 Me H F Et

164 H H OH Et

165 H H F Et

166 H Me OH Et

167 H Me F Et

168 Me H OH Et

169 Me H F Et

170 H H OH Et

171 H H F Et

172 H Me OH Et

173 H Me F Et

174 Me H OH Et

175 Me H F Et

176 H H OH Et

177 H H F Et

178 H Me OH Et

179 H Me F Et

180 Me H OH Et

181 Me H F Et

182 H H OH Et

183 H H F Et

184 H Me OH Et

185 H Me F Et

186 Me H OH Et

187 Me H F Et

188 H H OH Et

189 H H F Et

190 H Me OH Et

191 H Me F Et

192 Me H OH Et

193 Me H F Et

194 H H OH Et

195 H H F Et

196 H Me OH Et

197 H Me F Et

198 Me H OH Et

199 Me H F Et

200 H H OH i-Bu

201 H H F i-Bu

202 H Me OH i-Bu

203 H Me F i-Bu

204 Me H OH i-Bu

205 Me H F i-Bu

206 H H OH i-Bu

207 H H F i-Bu

208 H Me OH i-Bu

209 H Me F i-Bu

210 Me H OH i-Bu

211 Me H F i-Bu

212 H H OH i-Bu

213 H H F i-Bu

214 H Me OH i-Bu

215 H Me F i-Bu

216 Me H OH i-Bu

217 Me H F i-Bu

218 H H OH i-Bu

219 H H F i-Bu

220 H Me OH i-Bu

221 H Me F i-Bu

222 Me H OH i-Bu

223 Me H F i-Bu

224 H H OH i-Bu

225 H H F i-Bu

226 H Me OH i-Bu

227 H Me F i-Bu

228 Me H OH i-Bu

229 Me H F i-Bu

230 H H OH i-Bu

231 H H F i-Bu

232 H Me OH i-Bu

233 H Me F i-Bu

234 Me H OH i-Bu

235 Me H F i-Bu

236 H H OH i-Bu

237 H H F i-Bu

238 H Me OH i-Bu

239 H Me F i-Bu

240 Me H OH i-Bu

241 Me H F i-Bu

242 H H OH i-Bu

243 H H F i-Bu

244 H Me OH i-Bu

245 H Me F i-Bu

246 Me H OH i-Bu

247 Me H F i-Bu

248 H H OH i-Bu

249 H H F i-Bu

250 H Me OH i-Bu

251 H Me F i-Bu

252 Me H OH i-Bu

253 Me H F i-Bu

254 H H OH i-Bu

255 H H F i-Bu

256 H Me OH i-Bu

257 H Me F i-Bu

259 Me H OH i-Bu

260 Me H F i-Bu

Table 3 sets forth compounds of Formula (IV-1) wherein R₂, R₉, R₁₂, R₁₃,and B are delineated for each example in Table 3.

TABLE 3 (IV-1)

Example # R₂ R₉ R₁₂ R₁₃ B 261 OH Ph Me Me

262 F Ph Me Me

263 OH Ph Me Me

264 F Ph Me Me

265 OH Ph Me Me

266 F Ph Me Me

267 OH Ph Me Me

268 F Ph Me Me

269 OH Ph Me Me

270 F Ph Me Me

271 OH Ph Me Me

272 F Ph Me Me

273 OH Ph Me Me

274 F Ph Me Me

275 OH Ph Me Me

276 F Ph Me Me

277 OH Ph Me Me

278 F Ph Me Me

279 OH Ph Me Me

280 F Ph Me Me

281 OH 1-Naphthyl Me Me

282 F 1-Naphthyl Me Me

283 OH 1-Naphthyl Me Me

284 F 1-Naphthyl Me Me

285 OH 1-Naphthyl Me Me

286 F 1-Naphthyl Me Me

287 OH 1-Naphthyl Me Me

288 F 1-Naphthyl Me Me

289 OH 1-Naphthyl Me Me

290 F 1-Naphthyl Me Me

291 OH 1-Naphthyl Me Me

292 F 1-Naphthyl Me Me

293 OH 1-Naphthyl Me Me

294 F 1-Naphthyl Me Me

295 OH 1-Naphthyl Me Me

296 F 1-Naphthyl Me Me

297 OH 1-Naphthyl Me Me

298 F 1-Naphthyl Me Me

299 OH 1-Naphthyl Me Me

300 F 1-Naphthyl Me Me

301 OH Ph H Me

302 F Ph H Me

303 OH Ph H Me

304 F Ph H Me

305 OH Ph H Me

306 F Ph H Me

307 OH Ph H Me

308 F Ph H Me

309 OH Ph H Me

310 F Ph H Me

311 OH Ph H Me

312 F Ph H Me

313 OH Ph H Me

314 F Ph H Me

315 OH Ph H Me

316 F Ph H Me

317 OH Ph H Me

318 F Ph H Me

319 OH Ph H Me

320 F Ph H Me

321 OH 1-Naphthyl H Me

322 F 1-Naphthyl H Me

323 OH 1-Naphthyl H Me

324 F 1-Naphthyl H Me

325 OH 1-Naphthyl H Me

326 F 1-Naphthyl H Me

327 OH 1-Naphthyl H Me

328 F 1-Naphthyl H Me

329 OH 1-Naphthyl H Me

330 F 1-Naphthyl H Me

331 OH 1-Naphthyl H Me

332 F 1-Naphthyl H Me

333 OH 1-Naphthyl H Me

334 F 1-Naphthyl H Me

335 OH 1-Naphthyl H Me

336 F 1-Naphthyl H Me

337 OH 1-Naphthyl H Me

338 F 1-Naphthyl H Me

339 OH 1-Naphthyl H Me

340 F 1-Naphthyl H Me

341 OH Ph Me n-Pentyl

342 F Ph Me n-Pentyl

343 OH Ph Me n-Pentyl

344 F Ph Me n-Pentyl

345 OH Ph Me n-Pentyl

346 F Ph Me n-Pentyl

347 OH Ph Me n-Pentyl

348 F Ph Me n-Pentyl

349 OH Ph Me n-Pentyl

350 F Ph Me n-Pentyl

351 OH Ph Me n-Pentyl

352 F Ph Me n-Pentyl

353 OH Ph Me n-Pentyl

354 F Ph Me n-Pentyl

355 OH Ph Me n-Pentyl

356 F Ph Me n-Pentyl

357 OH Ph Me n-Pentyl

358 F Ph Me n-Pentyl

359 OH Ph Me n-Pentyl

360 F Ph Me n-Pentyl

361 OH 1-Naphthyl Me n-Pentyl

362 F 1-Naphthyl Me n-Pentyl

363 OH 1-Naphthyl Me n-Pentyl

364 F 1-Naphthyl Me n-Pentyl

365 OH 1-Naphthyl Me n-Pentyl

366 F 1-Naphthyl Me n-Pentyl

367 OH 1-Naphthyl Me n-Pentyl

368 F 1-Naphthyl Me n-Pentyl

369 OH 1-Naphthyl Me n-Pentyl

370 F 1-Naphthyl Me n-Pentyl

371 OH 1-Naphthyl Me n-Pentyl

372 F 1-Naphthyl Me n-Pentyl

373 OH 1-Naphthyl Me n-Pentyl

374 F 1-Naphthyl Me n-Pentyl

375 OH 1-Naphthyl Me n-Pentyl

376 F 1-Naphthyl Me n-Pentyl

377 OH 1-Naphthyl Me n-Pentyl

378 F 1-Naphthyl Me n-Pentyl

379 OH 1-Naphthyl Me n-Pentyl

380 F 1-Naphthyl Me n-Pentyl

381 OH Ph H n-Pentyl

382 F Ph H n-Pentyl

383 OH Ph H n-Pentyl

384 F Ph H n-Pentyl

385 OH Ph H n-Pentyl

386 F Ph H n-Pentyl

387 OH Ph H n-Pentyl

388 F Ph H n-Pentyl

389 OH Ph H n-Pentyl

390 F Ph H n-Pentyl

391 OH Ph H n-Pentyl

392 F Ph H n-Pentyl

393 OH Ph H n-Pentyl

394 F Ph H n-Pentyl

395 OH Ph H n-Pentyl

396 F Ph H n-Pentyl

397 OH Ph H n-Pentyl

398 F Ph H n-Pentyl

399 OH Ph H n-Pentyl

400 F Ph H n-Pentyl

401 OH 1-Naphthyl H n-Pentyl

402 F 1-Naphthyl H n-Pentyl

403 OH 1-Naphthyl H n-Pentyl

404 F 1-Naphthyl H n-Pentyl

405 OH 1-Naphthyl H n-Pentyl

406 F 1-Naphthyl H n-Pentyl

407 OH 1-Naphthyl H n-Pentyl

408 F 1-Naphthyl H n-Pentyl

409 OH 1-Naphthyl H n-Pentyl

410 F 1-Naphthyl H n-Pentyl

411 OH 1-Naphthyl H n-Pentyl

412 F 1-Naphthyl H n-Pentyl

413 OH 1-Naphthyl H n-Pentyl

414 F 1-Naphthyl H n-Pentyl

415 OH 1-Naphthyl H n-Pentyl

416 F 1-Naphthyl H n-Pentyl

417 OH 1-Naphthyl H n-Pentyl

418 F 1-Naphthyl H n-Pentyl

419 OH 1-Naphthyl H n-Pentyl

420 F 1-Naphthyl H n-Pentyl

421 OH Ph Me i-Pr

422 F Ph Me i-Pr

423 OH Ph Me i-Pr

424 F Ph Me i-Pr

425 OH Ph Me i-Pr

426 F Ph Me i-Pr

427 OH Ph Me i-Pr

428 F Ph Me i-Pr

429 OH Ph Me i-Pr

430 F Ph Me i-Pr

431 OH Ph Me i-Pr

432 F Ph Me i-Pr

433 OH Ph Me i-Pr

434 F Ph Me i-Pr

435 OH Ph Me i-Pr

436 F Ph Me i-Pr

437 OH Ph Me i-Pr

438 F Ph Me i-Pr

439 OH Ph Me i-Pr

440 F Ph Me i-Pr

441 OH 1-Naphthyl Me i-Pr

442 F 1-Naphthyl Me i-Pr

443 OH 1-Naphthyl Me i-Pr

444 F 1-Naphthyl Me i-Pr

445 OH 1-Naphthyl Me i-Pr

446 F 1-Naphthyl Me i-Pr

447 OH 1-Naphthyl Me i-Pr

448 F 1-Naphthyl Me i-Pr

449 OH 1-Naphthyl Me i-Pr

450 F 1-Naphthyl Me i-Pr

451 OH 1-Naphthyl Me i-Pr

452 F 1-Naphthyl Me i-Pr

453 OH 1-Naphthyl Me i-Pr

454 F 1-Naphthyl Me i-Pr

455 OH 1-Naphthyl Me i-Pr

456 F 1-Naphthyl Me i-Pr

457 OH 1-Naphthyl Me i-Pr

458 F 1-Naphthyl Me i-Pr

459 OH 1-Naphthyl Me i-Pr

460 F 1-Naphthyl Me i-Pr

461 OH Ph H i-Pr

462 F Ph H i-Pr

463 OH Ph H i-Pr

464 F Ph H i-Pr

465 OH Ph H i-Pr

466 F Ph H i-Pr

467 OH Ph H i-Pr

468 F Ph H i-Pr

469 OH Ph H i-Pr

470 F Ph H i-Pr

471 OH Ph H i-Pr

472 F Ph H i-Pr

473 OH Ph H i-Pr

474 F Ph H i-Pr

475 OH Ph H i-Pr

476 F Ph H i-Pr

477 OH Ph H i-Pr

478 F Ph H i-Pr

479 OH Ph H i-Pr

480 F Ph H i-Pr

481 OH 1-Naphthyl H i-Pr

482 F 1-Naphthyl H i-Pr

483 OH 1-Naphthyl H i-Pr

484 F 1-Naphthyl H i-Pr

485 OH 1-Naphthyl H i-Pr

486 F 1-Naphthyl H i-Pr

487 OH 1-Naphthyl H i-Pr

488 F 1-Naphthyl H i-Pr

489 OH 1-Naphthyl H i-Pr

490 F 1-Naphthyl H i-Pr

491 OH 1-Naphthyl H i-Pr

492 F 1-Naphthyl H i-Pr

493 OH 1-Naphthyl H i-Pr

494 F 1-Naphthyl H i-Pr

495 OH 1-Naphthyl H i-Pr

496 F 1-Naphthyl H i-Pr

497 OH 1-Naphthyl H i-Pr

498 F 1-Naphthyl H i-Pr

499 OH 1-Naphthyl H i-Pr

500 F 1-Naphthyl H i-Pr

501 OH Ph Me Benzyl

502 F Ph Me Benzyl

503 OH Ph Me Benzyl

504 F Ph Me Benzyl

505 OH Ph Me Benzyl

506 F Ph Me Benzyl

507 OH Ph Me Benzyl

508 F Ph Me Benzyl

509 OH Ph Me Benzyl

510 F Ph Me Benzyl

511 OH Ph Me Benzyl

512 F Ph Me Benzyl

513 OH Ph Me Benzyl

514 F Ph Me Benzyl

515 OH Ph Me Benzyl

516 F Ph Me Benzyl

517 OH Ph Me Benzyl

518 F Ph Me Benzyl

519 OH Ph Me Benzyl

520 F Ph Me Benzyl

521 OH 1-Naphthyl Me Benzyl

522 F 1-Naphthyl Me Benzyl

523 OH 1-Naphthyl Me Benzyl

524 F 1-Naphthyl Me Benzyl

525 OH 1-Naphthyl Me Benzyl

526 F 1-Naphthyl Me Benzyl

527 OH 1-Naphthyl Me Benzyl

528 F 1-Naphthyl Me Benzyl

529 OH 1-Naphthyl Me Benzyl

530 F 1-Naphthyl Me Benzyl

531 OH 1-Naphthyl Me Benzyl

532 F 1-Naphthyl Me Benzyl

533 OH 1-Naphthyl Me Benzyl

534 F 1-Naphthyl Me Benzyl

535 OH 1-Naphthyl Me Benzyl

536 F 1-Naphthyl Me Benzyl

537 OH 1-Naphthyl Me Benzyl

538 F 1-Naphthyl Me Benzyl

539 OH 1-Naphthyl Me Benzyl

540 F 1-Naphthyl Me Benzyl

541 OH Ph H Benzyl

542 F Ph H Benzyl

543 OH Ph H Benzyl

544 F Ph H Benzyl

545 OH Ph H Benzyl

546 F Ph H Benzyl

547 OH Ph H Benzyl

548 F Ph H Benzyl

549 OH Ph H Benzyl

550 F Ph H Benzyl

551 OH Ph H Benzyl

552 F Ph H Benzyl

553 OH Ph H Benzyl

554 F Ph H Benzyl

555 OH Ph H Benzyl

556 F Ph H Benzyl

557 OH Ph H Benzyl

558 F Ph H Benzyl

559 OH Ph H Benzyl

560 F Ph H Benzyl

561 OH 1-Naphthyl H Benzyl

562 F 1-Naphthyl H Benzyl

563 OH 1-Naphthyl H Benzyl

564 F 1-Naphthyl H Benzyl

565 OH 1-Naphthyl H Benzyl

566 F 1-Naphthyl H Benzyl

567 OH 1-Naphthyl H Benzyl

568 F 1-Naphthyl H Benzyl

569 OH 1-Naphthyl H Benzyl

570 F 1-Naphthyl H Benzyl

571 OH 1-Naphthyl H Benzyl

572 F 1-Naphthyl H Benzyl

573 OH 1-Naphthyl H Benzyl

574 F 1-Naphthyl H Benzyl

575 OH 1-Naphthyl H Benzyl

576 F 1-Naphthyl H Benzyl

577 OH 1-Naphthyl H Benzyl

578 F 1-Naphthyl H Benzyl

579 OH 1-Naphthyl H Benzyl

580 F 1-Naphthyl H Benzyl

581 OH Ph Me t-BuCH₂—

582 F Ph Me t-BuCH₂—

583 OH Ph Me t-BuCH₂—

584 F Ph Me t-BuCH₂—

585 OH Ph Me t-BuCH₂—

586 F Ph Me t-BuCH₂—

587 OH Ph Me t-BuCH₂—

588 F Ph Me t-BuCH₂—

589 OH Ph Me t-BuCH₂—

590 F Ph Me t-BuCH₂—

591 OH Ph Me t-BuCH₂—

592 F Ph Me t-BuCH₂—

593 OH Ph Me t-BuCH₂—

594 F Ph Me t-BuCH₂—

595 OH Ph Me t-BuCH₂—

596 F Ph Me t-BuCH₂—

597 OH Ph Me t-BuCH₂—

598 F Ph Me t-BuCH₂—

599 OH Ph Me t-BuCH₂—

600 F Ph Me t-BuCH₂—

601 OH 1-Naphthyl Me t-BuCH₂—

602 F 1-Naphthyl Me t-BuCH₂—

603 OH 1-Naphthyl Me t-BuCH₂—

604 F 1-Naphthyl Me t-BuCH₂—

605 OH 1-Naphthyl Me t-BuCH₂—

606 F 1-Naphthyl Me t-BuCH₂—

607 OH 1-Naphthyl Me t-BuCH₂—

608 F 1-Naphthyl Me t-BuCH₂—

609 OH 1-Naphthyl Me t-BuCH₂—

610 F 1-Naphthyl Me t-BuCH₂—

611 OH 1-Naphthyl Me t-BuCH₂—

612 F 1-Naphthyl Me t-BuCH₂—

613 OH 1-Naphthyl Me t-BuCH₂—

614 F 1-Naphthyl Me t-BuCH₂—

615 OH 1-Naphthyl Me t-BuCH₂—

616 F 1-Naphthyl Me t-BuCH₂—

617 OH 1-Naphthyl Me t-BuCH₂—

618 F 1-Naphthyl Me t-BuCH₂—

619 OH 1-Naphthyl Me t-BuCH₂—

620 F 1-Naphthyl Me t-BuCH₂—

621 OH Ph H t-BuCH₂—

622 F Ph H t-BuCH₂—

623 OH Ph H t-BuCH₂—

624 F Ph H t-BuCH₂—

625 OH Ph H t-BuCH₂—

626 F Ph H t-BuCH₂—

627 OH Ph H t-BuCH₂—

628 F Ph H t-BuCH₂—

629 OH Ph H t-BuCH₂—

630 F Ph H t-BuCH₂—

631 OH Ph H t-BuCH₂—

632 F Ph H t-BuCH₂—

633 OH Ph H t-BuCH₂—

634 F Ph H t-BuCH₂—

635 OH Ph H t-BuCH₂—

636 F Ph H t-BuCH₂—

637 OH Ph H t-BuCH₂—

638 F Ph H t-BuCH₂—

639 OH Ph H t-BuCH₂—

640 F Ph H t-BuCH₂—

641 OH 1-Naphthyl H t-BuCH₂—

642 F 1-Naphthyl H t-BuCH₂—

643 OH 1-Naphthyl H t-BuCH₂—

644 F 1-Naphthyl H t-BuCH₂—

645 OH 1-Naphthyl H t-BuCH₂—

646 F 1-Naphthyl H t-BuCH₂—

647 OH 1-Naphthyl H t-BuCH₂—

648 F 1-Naphthyl H t-BuCH₂—

649 OH 1-Naphthyl H t-BuCH₂—

650 F 1-Naphthyl H t-BuCH₂—

651 OH 1-Naphthyl H t-BuCH₂—

652 F 1-Naphthyl H t-BuCH₂—

653 OH 1-Naphthyl H t-BuCH₂—

654 F 1-Naphthyl H t-BuCH₂—

655 OH 1-Naphthyl H t-BuCH₂—

656 F 1-Naphthyl H t-BuCH₂—

657 OH 1-Naphthyl H t-BuCH₂—

658 F 1-Naphthyl H t-BuCH₂—

659 OH 1-Naphthyl H t-BuCH₂—

660 F 1-Naphthyl H t-BuCH₂—

Table 4 sets forth compounds of Formula (V-1) wherein R₂, R_(8a),R_(8b), R₁₄, and B are delineated for each example in Table 4.

TABLE 4 (V-1)

Example # R₂ R₁₄ NR_(8a)R_(8b) B 661 OH

662 F

663 OH

664 F

665 OH

666 F

667 OH

668 F

669 OH

670 F

671 OH

672 F

673 OH

674 F

675 OH

676 F

677 OH

678 F

679 OH

680 F

681 OH

682 F

683 OH

684 F

685 OH

686 F

687 OH

688 F

689 OH

690 F

691 OH

692 F

693 OH

694 F

695 OH

696 F

697 OH

698 F

699 OH

700 F

701 OH

702 F

703 OH

704 F

705 OH

706 F

707 OH

708 F

709 OH

710 F

711 OH

712 F

713 OH

714 F

715 OH

716 F

717 OH

718 F

719 OH

720 F

721 OH

722 F

723 OH

724 F

725 OH

726 F

727 OH

728 F

729 OH

730 F

731 OH

732 F

733 OH

734 F

735 OH

736 F

737 OH

738 F

739 OH

740 F

741 OH

742 F

743 OH

744 F

745 OH

746 F

747 OH

748 F

749 OH

750 F

751 OH

752 F

753 OH

754 F

755 OH

756 F

757 OH

758 F

759 OH

760 F

761 OH

762 F

763 OH

764 F

765 OH

766 F

767 OH

768 F

769 OH

770 F

771 OH

772 F

773 OH

774 F

775 OH

776 F

777 OH

778 F

779 OH

780 F

781 OH

782 F

783 OH

784 F

785 OH

786 F

787 OH

788 F

789 OH

790 F

791 OH

792 F

793 OH

794 F

795 OH

796 F

797 OH

798 F

799 OH

800 F

801 OH

802 F

803 OH

804 F

805 OH

806 F

807 OH

808 F

809 OH

810 F

811 OH

812 F

813 OH

814 F

815 OH

816 F

817 OH

818 F

819 OH

820 F

Table 5 sets forth compounds of Formula (VI-1) wherein R₂, R_(5a),R_(5b), R₆, and B are delineated for each example in Table 5.

TABLE 5 (VI-1)

Example # R₆ R_(5a) R_(5b) R₂ B 821 i-Pr H H OH

822 i-Pr H H F

823 i-Pr H Me OH

824 i-Pr H Me F

825 i-Pr Me H OH

826 i-Pr Me H F

827 i-Pr H H OH

828 i-Pr H H F

829 i-Pr H Me OH

830 i-Pr H Me F

831 i-Pr Me H OH

832 i-Pr Me H F

833 i-Pr H H OH

834 i-Pr H H F

835 i-Pr H Me OH

836 i-Pr H Me F

837 i-Pr Me H OH

838 i-Pr Me H F

839 i-Pr H H OH

840 i-Pr H H F

841 i-Pr H Me OH

842 i-Pr H Me F

843 i-Pr Me H OH

844 i-Pr Me H F

845 i-Pr H H OH

846 i-Pr H H F

847 i-Pr H Me OH

848 i-Pr H Me F

849 i-Pr Me H OH

850 i-Pr Me H F

851 i-Pr H H OH

852 i-Pr H H F

853 i-Pr H Me OH

854 i-Pr H Me F

855 i-Pr Me H OH

856 i-Pr Me H F

857 i-Pr H H OH

858 i-Pr H H F

859 i-Pr H Me OH

860 i-Pr H Me F

861 i-Pr Me H OH

862 i-Pr Me H F

863 i-Pr H H OH

864 i-Pr H H F

865 i-Pr Me Me OH

866 i-Pr H Me F

867 i-Pr H Me OH

868 i-Pr Me H F

869 i-Pr H H OH

870 i-Pr H H F

871 i-Pr H Me OH

872 i-Pr H Me F

873 i-Pr Me H OH

874 i-Pr Me H F

875 i-Pr H H OH

876 i-Pr H H F

877 i-Pr H Me OH

878 i-Pr H Me F

879 i-Pr Me H OH

880 i-Pr Me H F

881 Et H H OH

882 Et H H F

883 Et H Me OH

884 Et H Me F

885 Et Me H OH

886 Et Me H F

887 Et H H OH

888 Et H H F

889 Et H Me OH

890 Et H Me F

891 Et Me H OH

892 Et Me H F

893 Et H H OH

894 Et H H F

895 Et H Me OH

896 Et H Me F

897 Et Me H OH

898 Et Me H F

899 Et H H OH

900 Et H H F

901 Et H Me OH

902 Et H Me F

903 Et Me H OH

904 Et Me H F

905 Et H H OH

906 Et H H F

907 Et H Me OH

908 Et H Me F

909 Et Me H OH

910 Et Me H F

911 Et H H OH

912 Et H H F

913 Et H Me OH

914 Et H Me F

915 Et Me H OH

916 Et Me H F

917 Et H H OH

918 Et H H F

919 Et H Me OH

920 Et H Me F

921 Et Me H OH

922 Et Me H F

923 Et H H OH

924 Et H H F

925 Et H Me OH

926 Et H Me F

927 Et Me H OH

928 Et Me H F

929 Et H H OH

930 Et H H F

931 Et H Me OH

932 Et H Me F

933 Et Me H OH

934 Et Me H F

935 Et H H OH

936 Et H H F

937 Et H Me OH

938 Et H Me F

939 Et Me H OH

940 Et Me H F

In one embodiment of the invention, the 2′-chloroacetylenyl-substitutednucleoside derivatives of the invention are the isolated β-D or β-Lisomer. In another embodiment of the invention, the nucleosidederivative is in an enantiomeric mixture in which the desired enantiomeris at least 95%, 98% or 99% free of its enantiomer. In a preferredembodiment, the nucleoside derivatives are enantiomerically enriched.

In one embodiment of the present invention, the compounds of the formula(I) are in the β-D configuration. In an alternate embodiment of thepresent invention, the compounds of formula (I) are in the β-Lconfiguration.

The nucleoside derivatives depicted above are in the β-D configuration,however, it should be understood that the nucleoside derivatives can beeither in the β-L or β-D configuration.

The nucleoside derivatives of the present invention are biologicallyactive molecules that are useful in the treatment or prophylaxis ofviral infections, and in particular human immunodeficiency virus (HIV)and/or hepatitis B virus (HBV) infection. The compounds are also usefulfor the treatment of abnormal cellular proliferation, including tumorsand cancer. In another embodiment of the present invention, any of theactive compounds are useful in the treatment of HCV. One can easilydetermine the spectrum of activity by evaluating the compound in theassays described herein or with another confirmatory assay.

For instance, in one embodiment the efficacy of the antiviral compoundis measured according to the concentration of compound necessary toreduce the plaque number of the virus in vitro, according to methods setforth more particularly herein, by 50% (i.e. the compound's EC₅₀). Inpreferred embodiments the compound exhibits an EC₅₀ of less than 15 orpreferably, less than 10 micromolar in vitro.

In another embodiment, for the treatment or prophylaxis of a viralinfection, and in particular an HIV, HCV or HBV infection, in a host,the active compound or its derivative or salt can be administered incombination or alternation with another antiviral agent, such as ananti-HIV agent or anti-hepatitis agent, including those of the formulaabove. Alternatively, for the treatment of abnormal cellularproliferation, such as tumors and cancer, in a host, the active compoundor its derivative or salt can be administered in combination oralternation with another antiproliferative agent, such as ananti-neoplastic agent, including those of the formula above. In general,in combination therapy, effective dosages of two or more agents areadministered together, whereas during alternation therapy, an effectivedosage of each agent is administered serially. The dosages will dependon absorption, inactivation and excretion rates of the drug as well asother factors known to those skilled in the art. It is to be noted thatdosage values will also vary with the severity of the condition to bealleviated. It is to be further understood that for any particularsubject, specific dosage regimens and schedules should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions.

The compounds of the present invention can also be used to treat equineinfectious anemia virus (EIAV), feline immunodeficiency virus, andsimian immunodeficiency virus. (Wang, S., et al, “Activity of nucleosideand non-nucleoside reverse transcriptase inhibitors (NNRTI) againstequine infectious anemia virus (EIAV). “First National Conference onHuman Retroviruses and Related Infections, Washington, D.C., Dec. 12-16,1993; Sellon D. C., “Equine Infectious Anemia” Vet. Clin. North Am.Equine Pract. United States, 9: 321-336, 1993; Philpott, M. S., et al“Evaluation of 9-(2-phosphonylmethoxyethyl)adenine therapy for felineimmunodeficiency virus using a quantitative polymerase chain reaction”Vet. Immunol. Immunopathol. 35:155166, 1992.

The present invention also provides a pharmaceutical composition for thetreatment and/or prophylaxis of a viral infection, and in particular aHBV, HCV or HIV infection, in a host, preferably a human, comprising atherapeutically effective amount of an active compound of the presentinvention, optionally in a pharmaceutically acceptable carrier.

The present invention also provides a pharmaceutical composition for thetreatment and/or prophylaxis of an abnormal cellular proliferation, suchas tumors and cancer, in a host, preferably a human, comprising atherapeutically effective amount of an active compound of the presentinvention, optionally in a pharmaceutically acceptable carrier.

The present invention also provides a pharmaceutical composition for thetreatment and/or prophylaxis of a viral infection, and in particular aHBV, HCV or HIV infection, in a host, preferably a human, comprising atherapeutically effective amount of an active compound of the presentinvention, in combination with one or more other effective antiviralagent, and in particular an anti-HBV, anti-HCV or anti-HIV agent,optionally in a pharmaceutically acceptable carrier.

The present invention also provides a pharmaceutical composition for thetreatment and/or prophylaxis of an abnormal cellular proliferation, suchas tumors and cancer, in a host, preferably a human, comprising atherapeutically effective amount of an active compound of the presentinvention, in combination with one or more other effectiveantinroliferative agent, such as an antineoplastic agent, optionally ina pharmaceutically acceptable carrier.

The present invention also provides a method for the treatment and/orprophylaxis of a viral infection, and in particular a HBV, HCV or HIVinfection, in a host, preferably a human, comprising administering tothe host a therapeutically effective amount of an active compound of thepresent invention, optionally in a pharmaceutically acceptable carrier.

The present invention also provides a method for the treatment and/orprophylaxis of an abnormal cellular proliferation, such as tumors andcancer, in a host, preferably a human, comprising administering to thehost a therapeutically effective amount of an active compound of thepresent invention, optionally in a pharmaceutically acceptable carrier.

The present invention also provides a method for the treatment and/orprophylaxis of a viral infection, and in particular a HBV, HCV or HIVinfection, in a host, preferably a human, comprising administering tothe host a therapeutically effective amount of an active compound of thepresent invention, in combination and/or alternation with one or moreother effective antiviral agent, and in particular an anti-HBV, anti-HCVor anti-HIV agent, optionally in a pharmaceutically acceptable carrier.

The present invention also provides a method for the treatment and/orprophylaxis of an abnormal cellular proliferation, such as tumors andcancer, in a host, preferably a human, comprising administering to thehost a therapeutically effective amount of an active compound of thepresent invention, in combination and/or alternation with one or moreother effective antiproliferative agent, such as an antineoplasticagent, optionally in a pharmaceutically acceptable carrier.

The present invention also provides a use of an active compound of thepresent invention, optionally in a pharmaceutically acceptable carrier,for the treatment and/or prophylaxis of a viral infection, and inparticular a HBV, HCV or HIV infection, in a host, preferably a human.

The present invention also provides a use of an active compound of thepresent invention, optionally in a pharmaceutically acceptable carrier,for the treatment and/or prophylaxis of an abnormal cellularproliferation, such as tumors and cancer, in a host, preferably a human.

The present invention also provides a use of an active compound of thepresent invention, in combination and/or alternation with one or moreother effective antiviral agent, and in particular an anti-HBV, anti-HCVor anti-HIV agent, optionally in a pharmaceutically acceptable carrier,for the treatment and/or prophylaxis of a viral infection, and inparticular a HBV, HCV or HIV infection, in a host, preferably a human.

The present invention also provides a use of an active compound of thepresent invention, in combination and/or alternation with one or moreother effective antiproliferative agent, such as an antineoplasticagent, optionally in a pharmaceutically acceptable carrier, for thetreatment and/or prophylaxis of an abnormal cellular proliferation, suchas tumors and cancer, in a host, preferably a human.

The present invention also provides a use of an active compound of thepresent invention, optionally in a pharmaceutically acceptable carrier,in the manufacture of a medicament for the treatment and/or prophylaxisof a viral infection, and in particular a HBV, HCV or HIV infection, ina host, preferably a human.

The present invention also provides the use of an active compound of thepresent invention, optionally in a pharmaceutically acceptable carrier,in the manufacture of a medicament for the treatment and/or prophylaxisof an abnormal cellular proliferation, such as tumors and cancer, in ahost, preferably a human.

The present invention also provides the use of an active compound of thepresent invention, in combination and/or alternation with one or moreother effective antiviral agent, and in particular an anti-HBV, anti-HCVor anti-HIV agent, optionally in a pharmaceutically acceptable carrier,in the manufacture of a medicament for the treatment and/or prophylaxisof a viral infection, and in particular a HBV, HCV or HIV infection, ina host, preferably a human.

The present invention also provides the use of an active compound of thepresent invention, in combination and/or alternation with one or moreother effective antiproliferative agent, such as an antineoplasticagent, optionally in a pharmaceutically acceptable carrier, in themanufacture of a medicament for the treatment and/or prophylaxis of anabnormal cellular proliferation, such as tumors and cancer, in a host,preferably a human.

The invention also provides synthetic methods useful for preparing thecompounds of the invention, as well as intermediates disclosed hereinthat are useful in the preparation of the compounds of the presentinvention.

The invention as disclosed herein is method and composition for thetreatment of HIV, hepatitis B or C, or abnormal cellular proliferation,in humans or other host animals, that includes administering atherapeutically effective amount of a β-D- or β-L-nucleosidederivatives, a pharmaceutically acceptable derivative, including acompound which has been alkylated or acylated on sugar or phosphonatemoiety, or on the purine or pyrimidine, or a pharmaceutically acceptablesalt thereof, optionally in a pharmaceutically acceptable carrier. Thecompounds of this invention either possess antiviral (i.e., anti-HIV-1,anti-HIV-2, anti-hepatitis B/C virus) activity or antiproliferativeactivity, or are metabolized to a compound that exhibits such activity.The invention as disclosed herein also includes the process for thepreparation of such β-D- or β-L-nucleoside derivatives.

Stereoisomerism and Polymorphism

The compounds of the present invention may have asymmetric centers andoccur as racemates, racemic mixtures, individual diastereomers orenantiomers, with all isomeric forms being included in the presentinvention. Compounds of the present invention having a chiral center mayexist in and be isolated in optically active and racemic forms. Somecompounds may exhibit polymorphism. The present invention encompassesracemic, optically-active, polymorphic, or stereoisomeric form, ormixtures thereof, of a compound of the invention, which possess theuseful properties described herein. Optically active forms of thecompounds can be prepared using any method known in the art, includingbut not limited to by resolution of the racemic form byrecrystallization techniques, by synthesis from optically-activestarting materials; by chiral synthesis, or by chromatographicseparation using a chiral stationary phase or by enzymatic resolution.

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “aryl,” as used herein, refers to a mono- or polycycliccarbocyclic ring system containing at least one aromatic ring,including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl,indanyl, and indenyl.

The term “heteroaryl,” as used herein, refers to a mono- or polycyclicaromatic radical having one or more ring atom selected from S, O and N;and the remaining ring atoms are carbons, wherein any N or S containedwithin the ring may be optionally oxidized. Heteroaryl includes, but isnot limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzooxazolyl, quinoxalinyl.

In accordance with the invention, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group. Aromatic groups can be substituted or unsubstituted.

The terms “C₁-C₈ alkyl,” or “C₁-C₁₂ alkyl,” as used herein, refer tosaturated, straight- or branched-chain hydrocarbon radicals containingbetween one and eight, or one and twelve carbon atoms, respectively.Examples of C₁-C₈ alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl,n-hexyl, heptyl and octyl radicals; and examples of C₁-C₁₂ alkylradicals include, but are not limited to, ethyl, propyl, isopropyl,n-hexyl, octyl, decyl, dodecyl radicals.

The term “C₂-C₈ alkenyl,” or “C₂-C₂₀ alkenyl,” as used herein, refer tostraight- or branched-chain hydrocarbon radicals containing from two toeight carbon atoms having at least one carbon-carbon double bond by theremoval of a single hydrogen atom. Alkenyl groups include, but are notlimited to, for example, ethenyl, propenyl, butenyl,1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

The term “C₂-C₈ alkynyl,” or “C₂-C₂₀ alkynyl,” as used herein, refer tostraight- or branched-chain hydrocarbon radicals containing from two toeight carbon atoms having at least one carbon-carbon triple bond by theremoval of a single hydrogen atom. Representative alkynyl groupsinclude, but are not limited to, for example, ethynyl, 1-propynyl,1-butynyl, heptynyl, octynyl, and the like.

The term “C₃-C₈-cycloalkyl”, or “C₃-C₁₂-cycloalkyl,” as used herein,refers to a monocyclic or polycyclic saturated carbocyclic ringcompound. Examples of C₃-C₈-cycloalkyl include, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl andcyclooctyl; and examples of C₃-C₁₂-cycloalkyl include, but not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.

The terms “C₂-C₈ alkylene,” or “C₂-C₈ alkenylene,” as used herein, referto saturated or unsaturated respectively, straight- or branched-chainhydrocarbon di-radicals containing between two and eight carbon atoms,while the diradical may reside at the same or different carbon atoms.

The term “C₃-C₈ cycloalkenyl,” or “C₃-C₁₂ cycloalkenyl” as used herein,refers to monocyclic or polycyclic carbocyclic ring compound having atleast one carbon-carbon double bond. Examples of C₃-C₈ cycloalkenylinclude, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples ofC₃-C₁₂ cycloalkenyl include, but not limited to, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,and the like.

It is understood that any alkyl, alkenyl, alkynyl and cycloalkyl moietydescribed herein can also be an aliphatic group, an alicyclic group or aheterocyclic group. An “aliphatic” group is a non-aromatic moiety thatmay contain any combination of carbon atoms, hydrogen atoms, halogenatoms, oxygen, nitrogen or other atoms, and optionally contain one ormore units of unsaturation, e.g., double and/or triple bonds. Analiphatic group may be straight chained, branched or cyclic andpreferably contains between about 1 and about 24 carbon atoms, moretypically between about 1 and about 12 carbon atoms. In addition toaliphatic hydrocarbon groups, aliphatic groups include, for example,polyalkoxyalkyls, such as polyalkylene glycols, polyamines, andpolyimines, for example. Such aliphatic groups may be furthersubstituted.

The term “alicyclic,” as used herein, denotes a monovalent group derivedfrom a monocyclic or bicyclic saturated carbocyclic ring compound by theremoval of a single hydrogen atom. Examples include, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl,and bicyclo[2.2.2]octyl. Such alicyclic groups may be furthersubstituted.

The terms “heterocyclic” or “heterocycloalkyl” can be usedinterchangeably and referred to a non-aromatic ring or a bi- ortri-cyclic group fused system, where (i) each ring system contains atleast one heteroatom independently selected from oxygen, sulfur andnitrogen, (ii) each ring system can be saturated or unsaturated (iii)the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) thenitrogen heteroatom may optionally be quaternized, (v) any of the aboverings may be fused to an aromatic ring, and (vi) the remaining ringatoms are carbon atoms which may be optionally oxo-substituted.Representative heterocyclic groups include, but are not limited to,1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl,pyridazinonyl, and tetrahydrofuryl. Such heterocyclic groups may befurther substituted.

The term “substituted” refers to substitution by independent replacementof one, two, or three or more of the hydrogen atoms thereon withsubstituents including, but not limited to, —F, —Cl, —Br, —I, —OH,protected hydroxy, —NO₂, —N₃, —CN, —NH₂, protected amino, oxo, thioxo,—NH—C₁-C₁₂-alkyl, —NH—C₂-C₈-alkenyl, —NH—C₂-C₈-alkynyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₈-alkenyl, —O—C₂-C₈-alkynyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₈-alkenyl, —C(O)—C₂-C₈-alkynyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₈-alkenyl, —CONH—C₂-C₈-alkynyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₈-alkenyl,—OCO₂—C₂-C₈-alkynyl, —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₈-alkenyl, —OCONH—C₂-C₈-alkynyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH— heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₈-alkenyl, —NHC(O)—C₂-C₈-alkynyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₈-alkenyl,—NHCO₂—C₂-C₈-alkynyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂— heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₈-alkenyl,—NHC(O)NH—C₂-C₈-alkynyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₈-alkenyl,—NHC(S)NH—C₂-C₈-alkynyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₈-alkenyl,—NHC(NH)NH—C₂-C₈-alkynyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl, —NHC(NH)NH-aryl,—NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₈-alkenyl, —NHC(NH)—C₂-C₈-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₈-alkenyl, —C(NH)NH—C₂-C₈-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₈-alkenyl,—S(O)—C₂-C₈-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₈-alkenyl, SO₂NH—C₂-C₈-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH— heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₈-alkenyl, —NHSO₂—C₂-C₈-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₈-alkenyl, —S—C₂-C₈-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl. It is understood that the aryls, heteroaryls, alkyls,and the like can be further substituted.

The term “halogen,” as used herein, refers to an atom selected fromfluorine, chlorine, bromine and iodine.

The term “hydroxy activating group”, as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxyl groupso that it will depart during synthetic procedures such as in asubstitution or in an elimination reactions. Examples of hydroxylactivating group include, but not limited to, mesylate, tosylate,triflate, p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxy”, as used herein, refers to a hydroxy groupactivated with a hydroxyl activating group, as defined above, includingmesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, forexample.

The term “hydroxy protecting group” or “thiol protecting group,” as usedherein, refers to a labile chemical moiety which is known in the art toprotect a hydroxyl group or thiol against undesired reactions duringsynthetic procedures. After said synthetic procedure(s) the hydroxyprotecting group as described herein may be selectively removed. Hydroxyprotecting groups as known in the art are described generally in T. H.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons, New York (1999). Examples of hydroxylprotecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl,tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxyl protecting groups for the present invention areacetyl (Ac or —C(O)CH₃), benzoyl (Bz or —C(O)C₆H₅), and trimethylsilyl(TMS or —Si(CH₃)₃).

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “hydroxy prodrug group”, as used herein, refers to a promoietygroup which is known in the art to change the physicochemical, and hencethe biological properties of a parent drug in a transient manner bycovering or masking the hydroxy group. After said syntheticprocedure(s), the hydroxy prodrug group as described herein must becapable of reverting back to hydroxy group in vivo. Hydroxy prodruggroups as known in the art are described generally in Kenneth B. Sloan,Prodrugs, Topical and Ocular Drug Delivery, (Drugs and thePharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York(1992).

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the artare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of amino protecting groups include, but are not limitedto, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, andthe like.

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include chloro, bromo and iodogroups; sulfonic ester groups, such as mesylate, tosylate, brosylate,nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term “protic solvent’ as used herein, refers to a solvent that tendsto provide protons, such as an alcohol, for example, methanol, ethanol,propanol, isopropanol, butanol, t-butanol, and the like. Such solventsare well known to those skilled in the art, and it will be obvious tothose skilled in the art that individual solvents or mixtures thereofmay be preferred for specific compounds and reaction conditions,depending upon such factors as the solubility of reagents, reactivity ofreagents and preferred temperature ranges, for example. Furtherdiscussions of protogenic solvents may be found in organic chemistrytextbooks or in specialized monographs, for example: Organic SolventsPhysical Properties and Methods of Purification, 4th ed., edited by JohnA. Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, NY, 1986.

The term “hydrogen” includes deuterium. In general, the identificationof an element embraces the isotopes of the element, as suitable for thepreparation a pharmaceutical.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the Formula herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, 2^(nd) Ed. Wiley-VCH (1999); T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley andSons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The term “subject” as used herein refers to an animal. Preferably theanimal is a mammal. More preferably the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers, or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. Tautomers may be incyclic or acyclic. The configuration of any carbon-carbon double bondappearing herein is selected for convenience only and is not intended todesignate a particular configuration unless the text so states; thus acarbon-carbon double bond or carbon-heteroatom double bond depictedarbitrarily herein as trans may be cis, trans, or a mixture of the twoin any proportion.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, nontoxic acid addition salts are saltsof an amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of thepresent invention. “Prodrug”, as used herein means a compound which isconvertible in vivo by metabolic means (e.g. by hydrolysis) to acompound of the invention. Various forms of prodrugs are known in theart, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs,Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4,Academic Press (1985); Krogsgaard-Larsen, et al., (ed.). “Design andApplication of Prodrugs, Textbook of Drug Design and Development,Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug DeliverReviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975); Bernard Testa &Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002); and J.Rautio et al, “Prodrugs: design and clinical applications”, NatureReview—Drug Discovery, 7, 255-270 (2008).

The present invention also relates to solvates of the compounds ofFormula (I), for example hydrates.

It is to be understood that when a variable appears two or more times ina formula set forth herein, each occurrence of the variable isindependently selected from the identities set forth for that variable.

This invention also encompasses pharmaceutical compositions containing,and methods of treating viral infections through administering,pharmaceutically acceptable prodrugs of compounds of the invention. Forexample, compounds of the invention having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of the invention. The amino acidresidues include but are not limited to the 20 naturally occurring aminoacids commonly designated by three letter symbols and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

Pharmaceutical Compositions.

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminun hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to VanDevanter et al., U.S. Pat. No.5,508,269 to Smith et al., and WO 98/43,650 by Montgomery, all of whichare incorporated herein by reference). A discussion of pulmonarydelivery of antibiotics is also found in U.S. Pat. No. 6,014,969,incorporated herein by reference.

According to the methods of treatment of the present invention, viralinfections, conditions are treated or prevented in a patient such as ahuman or another animal by administering to the patient atherapeutically effective amount of a compound of the invention, in suchamounts and for such time as is necessary to achieve the desired result.

By a “therapeutically effective amount” of a compound of the inventionis meant an amount of the compound which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). A therapeutically effective amount ofthe compound described above may range from about 0.1 mg/Kg to about 500mg/Kg, preferably from about 1 to about 50 mg/Kg. Effective doses willalso vary depending on route of administration, as well as thepossibility of co-usage with other agents. It will be understood,however, that the total daily usage of the compounds and compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgment. The specific therapeuticallyeffective dose level for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; the activity of the specific compound employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination orcontemporaneously with the specific compound employed; and like factorswell known in the medical arts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

The compounds of the invention described herein can, for example, beadministered by injection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.1 toabout 500 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of atherapeutically effective amount of compound or compound composition toachieve the desired or stated effect. Typically, the pharmaceuticalcompositions of this invention will be administered from about 1 toabout 6 times per day or alternatively, as a continuous infusion. Suchadministration can be used as a chronic or acute therapy. The amount ofactive ingredient that may be combined with pharmaceutically exipientsor carriers to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. A typicalpreparation will contain from about 5% to about 95% active compound(w/w). Alternatively, such preparations may contain from about 20% toabout 80% active compound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

When the compositions of this invention comprise a combination of acompound of the invention described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds of this invention. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds of thisinvention in a single composition.

The said “additional therapeutic or prophylactic agents” includes butnot limited to, immune therapies (eg. interferon), therapeutic vaccines,antifibrotic agents, anti-inflammatory agents such as corticosteroids orNSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines(e.g. theophylline), mucolytic agents, anti-muscarinics,anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists),anti-oxidants (eg N-acetylcysteine), cytokine agonists, cytokineantagonists, lung surfactants and/or antimicrobial and anti-viral agents(eg ribavirin and amantidine). The compositions according to theinvention may also be used in combination with gene replacement therapy.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one of ordinary skill in theart. All publications, patents, published patent applications, and otherreferences mentioned herein are hereby incorporated by reference intheir entirety.

Pharmaceutically Acceptable Derivatives

The compound of the present invention can be administered as anyderivative that upon administration to the recipient is capable ofproviding directly or indirectly, the parent compound. Further, themodifications can affect the biological activity of the compound, insome cases increasing the activity over the parent compound. This caneasily be assessed by preparing the derivative and testing its antiviraland anti-proliferative activity according to the methods describedherein, or other method known to those skilled in the art.

In cases where compounds are suficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compound as apharmaceutically acceptable salt may be appropriate. Examples ofpharmaceutically acceptable salts are organic acid addition salts formedwith acids, which form a physiological acceptable anion, for example,tosylate, methanesulfonate, acetate, citrate, malonate, tartarate,succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate.Suitable inorganic salts may also be formed, including sulfate, nitrate,bicarbonate, and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

Any of the nucleosides described herein can be administrated as anucleotide prodrug to increase the activity, bioavailability, stabilityor otherwise alter the properties of the nucleoside. A number ofnucleotide prodrug ligands are known. In general, alkylation, acylationor other lipophilic modification of the mono, di or triphosphate of thenucleoside will increase the stability of the nucleotide. Examples ofsubstituent groups that can replace one or more hydrogens on thephosphate moiety are alkyl, aryl, steroids, carbohydrates, includingsugars, 1,2-diacylglycerol and alcohols. Many are described in R. Jonesand N. Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of thesecan be used in combination with the disclosed nucleosides to achieve adesired effect.

The active nucleoside can also be provided as a 5′-phosphoether lipid ora 5′-ether lipid, as disclosed in the following references, which areincorporated by reference herein: Kucera, L. S. et al 1990. “Novelmembrane interactive ether lipid analogs that inhibit infectious HIV-1production and induce defective virus formation.”AIDS Res. Hum. RetroViruses. 6:491-501; Piantadosi, C., J. et al 1991. “Synthesis andevaluation of novel ether lipid nucleoside conjugates for anti-HIVactivity.” J. Med. Chem. 34:1408.1414; Hosteller, K. Y. et al 1992.“Greatly enhanced inhibition of human immunodeficiency virus type 1replication in CEM and HT4-6C cells by 3′-deoxythymidine diphosphatedimyristoylglycerol, a lipid prodrug of 3′-deoxythymidine.” Antimicrob.Agents Chemother. 36:2025.2029; Hosetler, K. Y., et al 1990. “Synthesisand antiretroviral activity of phospholipid analogs of azidothymidineand other antiviral nucleosides.” J. Biol. Chem. 265:61127.

Nonlimiting examples of U.S. patents that disclose suitable lipophilicsubstituents that can be covalently incorporated into the nucleoside,preferably at the 5′-OH position of the nucleoside or lipophilicpreparations, include U.S. Pat. Nos. 5,149,794 (Sep. 22, 1992, Yatvin etal.); 5,194,654 (Mar. 16, 1993, Hostetler et al.), 5,223,263 (Jun. 29,1993, Hostetler et al.); 5,256,641 (Oct. 26, 1993, Yatvin et al.);5,411,947 (May 2, 1995, Hostetler et al.); 5,463,092 (Oct. 31, 1995,Hostetler et al.); 5,543,389 (Aug. 6, 1996, Yatvin et al.); 5,543,390(Aug. 6, 1996, Yatvin et al.); 5,543,391 (Aug. 6, 1996, Yatvin et al.);and 5,554,728 (Sep. 10, 1996; Basava et al.), all of which areincorporated herein by reference. Foreign patent publications thatdisclose lipophilic substituents that can be attached to the nucleosidesof the present invention, or lipophilic preparations, include WO89/02733, WO 90/00555, WO 91/16920, WO 91/18914, WO 93/00910, WO94/26273, WO 96/15132, EP 0 350 287, and WO 91/19721.

Nonlimiting examples of nucleotide prodrugs are described in thefollowing references: J. K. Dickson, Jr. et al, “Orally active squalenesynthetase inhibitors: bis((acyloxy)alkyl) prodrugs of theα-phosphonosylfonic acid moiety” J. Med. Chem. 1996, 39, 661-664; T.Kurz, et al, “Synthesis and antimalarial activity of chain substitutedpivaloyloxymethyl ester analogues of Fosmidomycin and FR900098” Bioorg.Med. Chem. 2006, 14, 5121-5135; J. E. Starrett, Jr. et al, “Synthesis,oral bioavilability determination, and in vitro evaluation of prodrugsof the antiviral agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA)” J.Med. Chem. 1994, 37, 1857-1864; H. T. Serafinowska, et al, “Synthesisand in vivo evaluation of prodrugs of9-[2-(phosphonomethoxy)ethoxy]adenine” J. Med. Chem. 1995, 38,1372-1379; S. Benzaria, et al, “Synthesis, in vitro antiviralevaluation, and stability studies of bis(S-acyl-2-thioethyl) esterderivatives of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) as potentialPMEA prodrugs with improved oral bioavailability” J. Med. Chem. 1996,39, 4958-4965; M. S. Louie and H. Chapman, “An efficient process for thesynthesis of cyclic HPMPC” Nucleosides,Nucleotides Nucleic acid 2001,20, 1099-1102; J.-R. Choi, et al, “A novel class of phosphonatenucleosides. 9-[(1-phosphonomethoxy)-cyclopropyl)methyl]guanine as apotent and selective anti-HBV agent” J. Med. Chem. 2004, 47, 2864-2869;M. Wu, et al, “Synthesis of9-[1-(substituted)-3-(phosphonomethoxy)propyl]adenine derivatives aspossible antiviral agents” Nucleosides,Nucleotides Nucleic acid. 2005,24, 1543-1568; X. Fu, et al, “Design and synthesis of novel bis(L-aminoacid) ester prodrugs of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) withimproved anti-HBV activity” Bioorg. Med. Chem. Lett. 2007, 17, 465-470.

Similarly, the 5′-phosphonate can also be provided as variousphosphonate prodrug to increase the activity, bioavailability, stabilityor otherwise alter the properties of the phosphonate. A number ofphosphonate prodrug ligands are known. In general, alkylation, acylationor other lipophilic modification of one or more hydroxy on thephosphonate moiety can be used to achieve a desired effect.

Combination and Alternation Therapy for HIV, HBV or HCV

It has been recognized that drug-resistant variants of HIV, HBV and HCVcan emerge after prolonged treatment with an antiviral agent. Drugresistance most typically occurs by mutation of a gene that encodes fora protein such as an enzyme used in viral replication, and mosttypically in the case of HIV, reverse transcriptase, protease, or DNApolymerase, and in the case of HBV, DNA polymerase, or in the case ofHCV, RNA polymerase, protease, or helicase. Recently, it has beendemonstrated that the efficacy of a drug against HIV infection can beprolonged, augmented, or restored by administering the compound incombination or alternation with a second, and perhaps third, antiviralcompound that induces a different mutation from that caused by theprinciple drug. Alternatively, the pharmacokinetics, biodistribution, orother parameter of the drug can be altered by such combination oralternation therapy. In general, combination therapy is typicallypreferred over alternation therapy because it induces multiplesimultaneous stresses on the virus.

The second antiviral agent for the treatment of HIV, in one embodiment,can be a reverse transcriptase inhibitor (a “RTI”), which can be eithera synthetic nucleoside (a “NRTI”) or a non-nucleoside compound (a“NNRTI”). In an alternative embodiment, in the case of HIV, the second(or third) antiviral agent can be a protease inhibitor. In otherembodiments, the second (or third) compound can be a pyrophosphateanalog, or a fusion binding inhibitor. A list compiling resistance datacollected in vitro and in vivo for a number of antiviral compounds isfound in Schinazi, et al, Mutations in retroviral genes associated withdrug resistance, International Antiviral News, 1997.

Preferred compounds for combination or alternation therapy for thetreatment of HBV include 3TC, FTC, L-FMAU, interferon, adefovirdipivoxil, entecavir, telbivudine (L-dT), valtorcitabine (3′-valinylL-dC), γ-D-dioxolanyl-guanine (DXG), β-D-dioxolanyl-2,6-diaminopurine(DAPD), and β-D-dioxolanyl-6-chloropurine (ACP), famciclovir,penciclovir, lobucavir, ganciclovir, and ribavirin.

Preferred examples of antiviral agents that can be used in combinationor alternation with the compounds disclosed herein for HIV therapyinclude cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane(FTC); the (−)-enantiomer of2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC); ziagen(abacavir), emtriva, viread (tenofovir DF), carbovir, acyclovir,foscarnet, interferon, AZT, DD1, D4T, CS-87(3′-azido-2′,3′-dideoxyuridine), and β-D-dioxolane nucleosides such asβ-D-dioxolanyl-guanine (DXG), β-D-dioxolanyl-2,6-diaminopurine (DAPD),and β-D-dioxolanyl-6-chloropurine (ACP), and integrase inhibitors suchas MK-0518.

Preferred protease inhibitors (PIs) include crixivan (indinavir),viracept (nelfinavir), norvir (ritonavir), invirase (saquinavir),aptivus (tipranavir), kaletra, lexiva (fosamprenavir), reyataz(atazanavir) and TMC-114.

Preferred Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)include rescripton (delavirdine), sustiva (efavirenz), viramune(nevirapine) and TMC-125.

Preferred Entry inhibitors include fuzeon (T-20), PRO-542, TNX-355,vicriviroc, aplaviroc and maraviroc.

A more comprehensive list of compounds that can be administered incombination or alternation with any of the disclosed nucleosides include(1S,4R)-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanolsuccinate (“1592”, a carbovir analog; GlaxoWellcome); 3TC:(+13-L-2′,3′-dideoxy-3′-thiacytidine (GlaxoWellcome); a-APA R18893:a-nitro-anilino-phenylacetamide; A-77003; C2 symmetry-based proteaseinhibitor (Abbott); A-75925: C2 symmetry-based protease inhibitor(Abbott); AAP-BHAP: bishetero-arylpiperazine analog (Upjohn); ABT-538:C2-symmetry-based protease inhibitor (Abbott); AzddU:3′-azido-2′,3′-dideoxyuridine; AZT: 3′-azido-3′-deoxythymidine(GlaxoWellcome); AZT-p-ddI:3′-azido-3′-deoxythymidilyl-(5′,5)-2′,3′-dideoxyinosinic acid (Ivax);BHAP: bisheteroaryl-piperazine; BILA 1906:N-{1S-[[[3-[2S-{(1,1-dimethylethyl)amino]carbonyl}-4R]-3-pyridinylmethyl)thio]-1-piperidinyl]-2R-hydroxy-1S-(phenylmethyl)-propyl]amino]-carbonyl]-2-methylpropyl}-2-quinolinecarboxamide(Bio Mega/Boehringer-Ingelheim); BILA 2185:N-(1,1-dimethylethyl)-1-[2S-[[2-2,6-dimethyphenoxy)-1-xoethyl]amino]-2R-hydroxy-4-phenylbutyl]-4R-pyridinylthio)-2-piperidinecarboxamide(BioMega/Boehringer-Ingelheim); BMS186,318: aminodiol derivative HIV-1protease inhibitor (Bristol-Myers-Squibb); d4API:9-[2,5-d]hydro-5-(phosphonomethoxy)-2-furanyladenine (Gilead); d4C:2′,3′-didehydro-2′,3′-dideoxycytidined; d4T:2′,3′-didehydro-3′-deoxythymidine (Bristol-Myers-Squibb); ddC;2′,3′-dideoxycytidine (Roche); ddI: 2′,3′-dideoxyinosine(Bristol-Myers-Squibb); DMP-266: a 1,4-dihydro-2H-3,1-benzoxazin-2-one;DMP-450:{[4R-(4-a,5-a,6-b,7-b)]-hexahydro-5,6-bis(hydroxy)-1,3-bis(3-amino)phenyl]-methyl)-4,7-bis-(phenylmethyl)-2H-1,3-diazepin-2-one}-bismesylate(Gilead); DXG: (−)-β-D-dioxolane-guanosine (Gilead); EBU-dM:5-ethyl-1-ethoxymethyl-6-(3,5-dimethylbenzyl)-uracil; E-EBU:5-ethyl-1-ethoxymethyl-6-benzyluracil; DS: dextran sulfate; E-EPSeU:1-(ethoxymethyl)-(6-phenylselenyl)-5-ethyluracil; E-EPU:1-(ethoxymethyl)-(6-phenylthio)-5-ethyluracil; FTC:β-2′,3′-dideoxy-5-fluoro-3′-thiacytidine (Gilead); HBY097:S-4-isopropoxycarbonyl-6-methoxy-3-(methylthio-methyl)-3,4-dihydroquinoxalin-2(1H)-thione;HEPT: 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine; HIV-1: humanimmunodeficiency virus type 1; JM2763:1,1′-(1,3-propanediyl)-bis-1,4,8,11-tetraaza-cyclotetradecane (JohnsonMatthey);JM3100:1,1′-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane(Johnson Matthey); KNI-272: (2S,3S)-3-amino-2-hydroxy-4-phenylbutyricacid-containing tripeptide; L-697,593;5-ethyl-6-methyl-3-(2-phthalimido-ethyl)pyridin-2(1H)-one; L-735,524:hydroxy-amino-pentane amide HIV-1 protease inhibitor (Merck); L-697,661:3-{[(4,7-dichloro-1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methylpyridin-2(1H)-one;L-FDDC: 0-O-L-5-fluoro-2′,3′-dideoxycytidine; L-FDOC:(−)-β-L-5-fluoro-dioxolane cytosine; MKC442:6-benzyl-1-ethoxymethyl-5-isopropyluracil (1-EBU; Mitsubishi);Nevirapine:11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyridol-[3,2-b:2′,3′-e]-diazepin-6-one(Boehringer-Ingelheim);NSC648400:1-benzyloxymethyl-5-ethyl-6-(alpha-pyridylthio)uracil(E-BPTU); P9941: [2-pyridylacetyl-IlePheAla-y(CHOH)]₂ (Dupont Merck);PFA: phosphonoformate (foscarnet; Astra); PMEA:9-(2-phosphonylmethoxyethyl)adenine (Gilead); PMPA:(R)-9-(2-phosphonylmethoxypropyl)adenine (Gilead); Ro 31-8959:hydroxyethylamine derivative HIV-1 protease inhibitor (Roche); RPI-312:peptidyl protease inhibitor,1-[(3S)-3-(n-alpha-benzyloxycarbonyl)-1-asparginyl)-amino-2-hydroxy-4-phenylbutyryl]-n-tert-1-prolineamide; 2720:6-chloro-3,3-dimethyl-4-(isopropenyloxycarbonyl)-3,4-dihydro-quinoxalin-2-(1H)-thione;SC-52151: hydroxy-ethylurea isostere protease inhibitor (Searle);SC-55389A: hydroxyethyl-urea isostere protease inhibitor (Searle); TIBOR82150:(+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)-imidazo[4,5,1-jk]-[1,4]benzodiazepin-2(1H)-thione(Janssen); TIBO 82913:(+)-(5s)-4,5,6,7,-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,ljk]-[1,4]benzo-diazepin-2(1H)-thione(Janssen); TSAO-m3T:[2′,5′-bis-O-(tert-butyl-dimethylsilyl)-3′-spiro-5′-(4′-amino-1′,2′-oxathiole-2′,2′-dioxide)]-β-D-pento-furanosyl-N-3-methylthymine;U90152:1-[3-[(1-methylethyl)-amino]-2-pyridinyl]-4-[[5-[(methylsulphonyl)-amino]-1H-indol-2-yl]carbonyl]piperazine;UC: thiocarboxanilide derivatives (Uniroyal); UC-781:N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothioamide;UC-82:N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-thiophenecarbothioamide;VB 11,328: hydroxyethyl-sulphonamide protease inhibitor (Vertex);VX-478: hydroxyethylsulphonamide protease inhibitor (Vertex); XM 323:cyclic urea protease inhibitor (Dupont Merck).

The active compound can also be administered in combination oralternation with ribavarin, interferon, interleukin or a stabilizedprodrug of any of them. More broadly described, the compound can beadministered in combination or alternation with any of the anti-HCVdrugs listed below.

Table of anti-Hepatitis C Compounds in Current Clinical DevelopmentPharmaceutical Drug name Drug category Company PEGASYS Long actinginterferon Roche pegylated interferon alfa-2a INFERGEN Long actinginterferon InterMune interferon alfacon-1 OMNIFERON Long actinginterferon Viragen natural interferon ALBUFERON Long acting interferonHuman Genome Sciences REBIF Interferon Ares-Serono interferon beta-laOmega Interferon Interferon BioMedicine Oral Interferon alpha OralInterferon Amarillo Biosciences Interferon gamma-lb Anti-fibroticInterMune IP-501 Anti-fibrotic InterMune Merimebodib VX-497 IMPDHinhibitor Vertex (inosine monophosphate dehydrogenase) AMANTADINE BroadAntiviral Agent Endo Labs (Symmetrel) Solvay IDN-6556 Apotosisregulation Idun Pharma. XTL-002 Monclonal Antibody XTL HCV/MF59 VaccineChiron CIVACIR Polyclonal Antibody NABI Therapeutic vaccine InnogeneticsVIRAMIDINE Nucleoside Analogue ICN ZADAXIN Immunomodulator Sci Clone(thymosin alfa-1) CEPLENE (histamine) Immunomodulator Maxim telaprevirProtease inhibitor Vertex Boceprevir Protease inhibitor Merck ISIS 14803Antisense Isis Pharmaceutical/Elan IDN-6556 Caspase inhibitor IdunPharmaceuticals JTK 003 Polymerase Inhibitor AKROS Pharma TarvacinAnti-Phospholipid Peregrine Therapy HCV-796 Polymerase InhibitorViroPharma/Wyeth CH-6 Protease inhibitor Schering ANA971 IsatoribineANADYS ANA245 Isatoribine ANADYS CPG 10101 (Actilon) ImmunomodulatorColey Rituximab (Rituxam) Anti-CD2O Genetech/IDEC Monoclonal AntibodyNM283 (Valopicitabine) Polymerase Inhibitor Idenix PharmaceuticalsHepX ™-C Monoclonal Antibody XTL IC41 Therapeutic Vaccine IntercellMedusa Interferon Longer acting interferon Flame1 Technologies E-1Therapeutic Vaccine Innogenetics Multiferon Long Acting InterferonViragen BILN 2061 Serine Protease inhibitor Boehringer-IngelheimTMC435350 Serine Protease inhibitor Tibotec nitazoxanide To bedetermined Romark R7128/PSI6130 Polymerase Inhibitor Roche/PharmassetPSI7977 Polymerase Inhibitor Pharmasset PSI938 Polymerase InhibitorPharmasset IDX184 Polymerase Inhibitor Idenix R1626 Polymerase inhibitorRoche MK-7009 protease inhibitor Merck ITMN-191 protease inhibitorInterMune Debio 025 Cyclophilin inhibitor Debiopharm SCY-635 Cyclophilininhibitor Scynexis BMS-790052 NS5A inhibitor Bristol-Myers SquibbBMS-791325 protease inhibitor Bristol-Myers Squibb INX-189 PolymeraseInhibitor InhibitexCombination Therapy for the Treatment of Proliferative Conditions

In another embodiment, the compounds, when used as an antiproliferative,can be administered in combination with another compound that increasesthe effectiveness of the therapy, including but not limited to anantifolate, a 5-fluoropyrimidine (including 5-fluorouracil), a cytidineanalogue such as β-L-1,3-dioxolanyl cytidine or β-L-1,3-dioxolanyl5-fluorocytidine, antimetabolites (including purine antimetabolites,cytarabine, fudarabine, floxuridine, 6-mercaptopurine, methotrexate, and6-thioguanine), hydroxyurea, mitotic inhibitors (including CPT-11,Etoposide (VP-21), taxol, and vinca alkaloids such as vincristine andvinblastine, an alkylating agent (including but not limited to busulfan,chlorambucil, cyclophosphamide, ifofamide, mechlorethamine, melphalan,and thiotepa), nonclassical alkylating agents, platinum containingcompounds, bleomycin, an anti-tumor antibiotic, an anthracycline such asdoxorubicin and dannomycin, an anthracenedione, topoisomerase IIinhibitors, hormonal agents (including but not limited tocorticosteroids (dexamethasone, prednisone, and methylprednisone),androgens such as fluoxymesterone and methyltestosterone, estrogens suchas diethylstilbesterol, antiestrogens such as tamoxifen, LHRH analoguessuch as leuprolide, antiandrogens such as flutamide, aminoglutethimide,megestrol acetate, and medroxyprogesterone), asparaginase, carmustine,lomustine, hexamethyl-melamine, dacarbazine, mitotane, streptozocin,cisplatin, carboplatin, levamasole, and leucovorin. The compounds of thepresent invention can also be used in combination with enzyme therapyagents and immune system modulators such as an interferon, interleukin,tumor necrosis factor, macrophage colony-stimulating factor and colonystimulating factor.

Although the invention has been described with respect to variouspreferred embodiments, it is not intended to be limited thereto, butrather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

Antiviral Activity

An inhibitory amount or dose of the compounds of the present inventionmay range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively fromabout 1 to about 100 mg/Kg. Inhibitory amounts or doses will also varydepending on route of administration, as well as the possibility ofco-usage with other agents.

According to the methods of treatment of the present invention, viralinfections are treated or prevented in a subject such as a human orlower mammal by administering to the subject an anti-hepatitis C virallyeffective amount or an inhibitory amount of a compound of the presentinvention, in such amounts and for such time as is necessary to achievethe desired result. An additional method of the present invention is thetreatment of biological samples with an inhibitory amount of a compoundof composition of the present invention in such amounts and for suchtime as is necessary to achieve the desired result.

The term “anti-hepatitis C virally effective amount” of a compound ofthe invention, as used herein, mean a sufficient amount of the compoundso as to decrease the viral load in a biological sample or in a subject(e.g., resulting in at least 10%, preferably at least 50%, morepreferably at least 80%, and most preferably at least 90% or 95%,reduction in viral load). As well understood in the medical arts, ananti-hepatitis C virally effective amount of a compound of thisinvention will be at a reasonable benefit/risk ratio applicable to anymedical treatment.

The term “inhibitory amount” of a compound of the present inventionmeans a sufficient amount to decrease the hepatitis C viral load in abiological sample or a subject (e.g., resulting in at least 10%,preferably at least 50%, more preferably at least 80%, and mostpreferably at least 90% or 95%, reduction in viral load). It isunderstood that when said inhibitory amount of a compound of the presentinvention is administered to a subject it will be at a reasonablebenefit/risk ratio applicable to any medical treatment as determined bya physician. The term “biological sample(s),” as used herein, means asubstance of biological origin intended for administration to a subject.Examples of biological samples include, but are not limited to, bloodand components thereof such as plasma, platelets, subpopulations ofblood cells and the like; organs such as kidney, liver, heart, lung, andthe like; sperm and ova; bone marrow and components thereof; or stemcells. Thus, another embodiment of the present invention is a method oftreating a biological sample by contacting said biological sample withan inhibitory amount of a compound or pharmaceutical composition of thepresent invention.

Upon improvement of a subject's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease. Thesubject may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific inhibitory dose for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; the activity of the specific compound employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts.

The total daily inhibitory dose of the compounds of this inventionadministered to a subject in single or in divided doses can be inamounts, for example, from 0.01 to 50 mg/kg body weight or more usuallyfrom 0.1 to 25 mg/kg body weight. Single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose. Ingeneral, treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one with ordinary skill inthe art. All publications, patents, published patent applications, andother references mentioned herein are hereby incorporated by referencein their entirety.

Antiviral Activity

An inhibitory amount or dose of the compounds of the present inventionmay range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively fromabout 1 to about 100 mg/Kg. Inhibitory amounts or doses will also varydepending on route of administration, as well as the possibility ofco-usage with other agents.

According to the methods of treatment of the present invention, viralinfections are treated or prevented in a subject such as a human orlower mammal by administering to the subject an anti-hepatitis C virallyeffective amount or an inhibitory amount of a compound of the presentinvention, in such amounts and for such time as is necessary to achievethe desired result. An additional method of the present invention is thetreatment of biological samples with an inhibitory amount of a compoundof composition of the present invention in such amounts and for suchtime as is necessary to achieve the desired result.

The term “anti-hepatitis C virally effective amount” of a compound ofthe invention, as used herein, mean a sufficient amount of the compoundso as to decrease the viral load in a biological sample or in a subject(e.g., resulting in at least 10%, preferably at least 50%, morepreferably at least 80%, and most preferably at least 90% or 95%,reduction in viral load). As well understood in the medical arts, ananti-hepatitis C virally effective amount of a compound of thisinvention will be at a reasonable benefit/risk ratio applicable to anymedical treatment.

The term “inhibitory amount” of a compound of the present inventionmeans a sufficient amount to decrease the hepatitis C viral load in abiological sample or a subject (e.g., resulting in at least 10%,preferably at least 50%, more preferably at least 80%, and mostpreferably at least 90% or 95%, reduction in viral load). It isunderstood that when said inhibitory amount of a compound of the presentinvention is administered to a subject it will be at a reasonablebenefit/risk ratio applicable to any medical treatment as determined bya physician. The term “biological sample(s),” as used herein, means asubstance of biological origin intended for administration to a subject.Examples of biological samples include, but are not limited to, bloodand components thereof such as plasma, platelets, subpopulations ofblood cells and the like; organs such as kidney, liver, heart, lung, andthe like; sperm and ova; bone marrow and components thereof; or stemcells. Thus, another embodiment of the present invention is a method oftreating a biological sample by contacting said biological sample withan inhibitory amount of a compound or pharmaceutical composition of thepresent invention.

Upon improvement of a subject's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease. Thesubject may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific inhibitory dose for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; the activity of the specific compound employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts.

The total daily inhibitory dose of the compounds of this inventionadministered to a subject in single or in divided doses can be inamounts, for example, from 0.01 to 50 mg/kg body weight or more usuallyfrom 0.1 to 25 mg/kg body weight. Single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose. Ingeneral, treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one with ordinary skill inthe art. All publications, patents, published patent applications, andother references mentioned herein are hereby incorporated by referencein their entirety.

Abbreviations

Abbreviations which may be used in the descriptions of the scheme andthe examples that follow are: Ac for acetyl; AcOH for acetic acid; AIBNfor azobisisobutyronitrile; BINAP for2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Boc₂O fordi-tert-butyl-dicarbonate; Boc for t-butoxycarbonyl; Bpoc for1-methyl-1-(4-biphenylyl)ethyl carbonyl; Bz for benzoyl; Bn for benzyl;BocNHOH for tert-butyl N-hydroxycarbamate; t-BuOK for potassiumtert-butoxide; Bu₃SnH for tributyltin hydride; BOP for(benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumHexafluorophosphate; Brine for sodium chloride solution in water; CDIfor carbonyldiimidazole; CH₂Cl₂ for dichloromethane; CH₃ for methyl;CH₃CN for acetonitrile; Cs₂CO₃ for cesium carbonate; CuCl for copper (I)chloride; CuI for copper (I) iodide; dba for dibenzylidene acetone; dppbfor diphenylphosphino butane; DBU for1,8-diazabicyclo[5.4.0]undec-7-ene; DCC forN,N′-dicyclohexylcarbodiimide; DEAD for diethylazodicarboxylate; DIADfor diisopropyl azodicarboxylate; DIPEA or (i-Pr)₂EtN forN,N,-diisopropylethyl amine; Dess-Martin periodinane for1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one; DMAP for4-dimethylaminopyridine; DME for 1,2-dimethoxyethane; DMF forN,N-dimethylformamide; DMSO for dimethyl sulfoxide; DMT fordi(p-methoxyphenyl)phenylmethyl or dimethoxytrityl; DPPA fordiphenylphosphoryl azide; EDC forN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide; EDC HCl forN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; EtOAc forethyl acetate; EtOH for ethanol; Et₂O for diethyl ether; HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluroniumHexafluorophosphate; HCl for hydrogen chloride; HOBT for1-hydroxybenzotriazole; K₂CO₃ for potassium carbonate; n-BuLi forn-butyl lithium; i-BuLi for i-butyl lithium; t-BuLi for t-butyl lithium;PhLi for phenyl lithium; LDA for lithium diisopropylamide; LiTMP forlithium 2,2,6,6-tetramethylpiperidinate; MeOH for methanol; Mg formagnesium; MOM for methoxymethyl; Ms for mesyl or —SO₂—CH₃; Ms₂O formethanesulfonic anhydride or mesyl-anhydride; NaN(TMS)₂ for sodiumbis(trimethylsilyl)amide; NaCl for sodium chloride; NaH for sodiumhydride; NaHCO₃ for sodium bicarbonate or sodium hydrogen carbonate;Na₂CO₃ sodium carbonate; NaOH for sodium hydroxide; Na₂SO₄ for sodiumsulfate; NaHSO₃ for sodium bisulfite or sodium hydrogen sulfite; Na₂S₂O₃for sodium thiosulfate; NH₂NH₂ for hydrazine; NH₄HCO₃ for ammoniumbicarbonate; NH₄Cl for ammonium chloride; NMMO for N-methylmorpholineN-oxide; NaIO₄ for sodium periodate; Ni for nickel; OH for hydroxyl;OsO₄ for osmium tetroxide; TBAF for tetrabutylammonium fluoride; TEA orEt₃N for triethylamine; TFA for trifluoroacetic acid; THF fortetrahydrofuran; TMEDA for N,N,N′,N′-tetramethylethylenediamine; TPP orPPh₃ for triphenyl-phosphine; Troc for 2,2,2-trichloroethyl carbonyl; Tsfor tosyl or —SO₂—C₆H₄—CH₃; Ts₂O for tolylsulfonic anhydride ortosyl-anhydride; TsOH for p-tolylsulfonic acid; Pd for palladium; Ph forphenyl; POPd for dihydrogendichlorobis(di-tert-butylphosphinito-KP)palladate(II); Pd₂(dba)₃ fortris(dibenzylideneacetone) dipalladium (0); Pd(PPh₃)₄ fortetrakis(triphenylphosphine)palladium (0); PdCl₂(PPh₃)₂ fortrans-dichlorobis-(triphenylphosphine)palladium (II); Pt for platinum;Rh for rhodium; Ru for ruthenium; TBS for tert-butyl dimethylsilyl; TMSfor trimethylsilyl; or TMSC1 for trimethylsilyl chloride.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared. These schemes are of illustrative purpose, and are not meantto limit the scope of the invention. Equivalent, similar, or suitablesolvents, reagents or reaction conditions may be substituted for thoseparticular solvents, reagents, or reaction conditions described hereinwithout departing from the general scope of the method of synthesis.

The syntheses of various nucleoside analogs have been well documented inthe literature, the following reviews are incorporated hereinwith byreferences: D. M. Huryn and M. Okabe, Chem. Rev. 1992, 92, 1745; K. W.Pankiewicz, Carbohydrate Research, 2000, 327, 87-105; G. Gumina et al,Antiviral Nucleosides: Chiral Synthesis and Chemotherapy, C. K. Chu(Ed.), Elsevier, 2003, pages 1-76 and 77-189; nucleoside analogs used asantimetabolites have been summarized: M. M. Mader and J. R. Henry,Comprehensive Medicinal Chemistry II, Elsevier, 2007, Vol 7, pages55-79; nucleoside analogs used as antiviral agents have been summarized:Comprehensive Medicinal Chemistry II, Elsevier, 2007, Vol 7, pages295-327 by E. Littler and X-X Zhou; and pages 338-343 by T. A. Lyle; andpages 398-400 by U. Schmitz et al. The synthesis of each of theseindividual analog can be found in the literatures cited therein.Nonlimiting examples of process are also incoporated hereinwith byreference: Clark et al, J. Med. Chem. 2005, 48, 5504; Clark et al,Bioorg. Med. Chem. Lett. 2006, 16, 1712; Clark et al, J. Carbohydr.Chem. 2006, 25, 461; Seela et al, Org. Biomol. Chem. 2008, 6, 596; Panet al, J. Org. Chem. 1999, 94, 4; Shi et al, Bioorg. Med. Chem. 2005,13, 1641; He et al, J. Org. Chem. 2003, 68, 5519; Gudmundsson et al, J.Med. Chem. 2000, 43, 2473; Jean-Baptiste et al, Synlett 2008, 817;Wilson et al, Synthesis 1995, 1465; Lin et al, J. Med. Chem. 1991, 34,2607; Matsuda et al, J. Med. Chem. 1991, 34, 812; Robins et al, J. Med.Chem. 1992, 35, 2283; Serafinowski et al, Tetrahedron 1996, 52, 7929;Serafinowski et al, Tetrahedron 2000, 56, 333; Houlton et al,Tetrahedron 1993, 49, 8087; Serafinowski et al, Synthesis 1997, 225;McCarthy et al, Tetrahedron 1996, 52, 45; Schmit, Synlett 1994, 241;Hirota et al, ChemComm 1999, 1827; Babu et al, Org. Biomol. Chem. 2003,1, 3514; Samano et al, J. Am. Chem. Soc. 1992, 114, 4007; Beard et al,Carbohydrate Res. 1990, 87; Wigerinck et al, J. Med. Chem. 1991, 34,2383; Ye et al, J. Org. Chem. 2005, 70, 7902; Eldrup et al, J. Med.Chem. 2004, 47, 2283 and 5284; Tang et al, J. Org. Chem. 1999, 64, 747;Jeannot et al, Org. Biomol. Chem. 2003, 1, 2096; Li et al, Org. Lett.2001, 3, 1025; Marcotte et al, Synthesis 2001, 929; Dai et al, Org.Lett. 2001, 3, 807; Yoshimura et al, Bioorg. Med. Chem. Lett. 1994, 4,721; Ohtawa et al, J. Med. Chem. 2007, 50, 2007; McGee et al, J. Org.Chem. 1996, 61, 781; Ogamino et al, J. Org. Chem. 2005, 70, 1684;Ichikawa et al, Org. Biomol. Chem. 2006, 4, 1284; Pan et al, J. Org.Chem. 1999, 64, 4; Huang et al, J. Med. Chem. 1991, 34, 1640; Kodama etal, Tetrahedron 2006, 62, 10011; He et al, J. Org. Chem. 2003, 68, 5519;Kumamoto et al, J. Med. Chem. 2006, 49, 7861; and Haraguchi et al, Org.Lett. 2004, 6, 2645.

General procedure to prepare 2′-chloroacetylenyl nucleoside of presentinvention is depicted in scheme 1. The ketone compound (1-2), herein P₁,P₂ and P₃ are hydroxyl protection group, such as but not limited to,benzoyl, acetyl, TMS, TIPS, was made from 2-hydroxy compound (1-1)according to the modified procedure from the account by Cook, G. P;Greenberg, M. M. J. Org. Chem. 1994, 59, 4704. The addition ofchloroacetylene to ketone has also been well described in the patent,U.S. Pat. No. 3,290,297 by Cross, A. D. The ketone compound (1-2) wastreated with the intermediate generated from 1,2-dichloroethylene andmethyllithium in the presence of metal halides such as, but not limitedto, CeCl₃, in aprotic solvent such as diethyl ether, THF, DME, followedby protection of resulting 2′-hydroxy group with P₄, such as but notlimited to, benzoyl, acetyl, TMS, TIPS to give the chloroacetylenylcompound (1-3) in good yield.

A more thorough discussion of the procedures, reagents and conditionsfor protecting hydroxyl group is described in literature, for example,by T. W. Greene and P. G. M. Wuts in “Protective Groups in OrganicSynthesis” 3rded., John Wiley & Son, Inc., 1999.

Further glycosylation of the nucleobase (1-3) was accomplished bytreatment of the compound (1-3) with the appropriate persilylatednucleobase in the presence of a Lewis acid such as, but not limited to,SnCl₄, TiCl₄, TMSOTf, HgO or HgBr₂ in an aprotic solvent such as, butnot limited to, toluene, acetonitrile, benzene, THF, DME, or a mixtureof any or all of these solvents. The reaction temperature was from roomtemperature to 150° C. The optional protecting groups in the protectednucleosides or the compound formula (1-4) can be cleaved followingestablished deprotection methodologies. A more thorough discussion ofthe procedures, reagents and conditions for deprotection is described inliterature, for example, by T. W. Greene and P. G. M. Wuts in“Protective Groups in Organic Synthesis” 3rded., John Wiley & Son, Inc.,1999.

The synthesis of nucleoside 5′-monophosphate prodrugs have also beenwell documented in the literature, see references cited in accounts byCahard et al, Mini-Reviews Med. Chem. 2004, 4, 371; Meier et al,Mini-Reviews Med. Chem. 2004, 4, 383; Peyrottes et al, Mini-Reviews Med.Chem. 2004, 4, 395; Drontle et al, Mini-Reviews Med. Chem. 2004, 4, 409;and nonlimiting examples of recent process: Gisch et al, J. Med. Chem.2007, 50, 1658; Boyer et al, J. Med. Chem. 2006, 49, 7711; Khamnei etal, J. Med. Chem. 1996, 39, 4109; Li et al, Synlett 2004, 2600; Perroneet al, J. Med. Chem. 2007, 50, 5463; Gisch et al, J. Med. Chem. 2007,50, 1658 and 1840; Hecker et al, J. Med. Chem. 2007, 50, 3891; Prakashet al, J. Med. Chem. 2005, 48, 1199; and Gunic et al, Bioorg. Med. Chem.Lett. 2007, 17, 2452 (for 3′,5′-cyclic monophosphate prodrug).

The synthesis of nucleoside phosphonates and/or their prodrugs have alsobeen well documented in the literature, see references cited in accountsby Hecker et al, J. Med. Chem. 2008, 51, 2328; Krise et al, Adv. DrugDeliv. Rev. 1996, 19, 287; Berkowitz et al, J. Fluorine Chem. 2001, 112,13; Romanenko et al, Chem. Rev.2006, 106, 3868; De Clercq, AntiviralRes. 2007, 75, 1; De Clercq et al, Nat. Rev.—Drug Disc. 2005, 4, 928;and nonlimiting examples of recent process: Mackman et al, Bioorg. Med.Chem. 2007, 15, 5519; Dang et al, Bioorg. Med. Chem. Lett. 2007, 17,3412; Meier et al, J. Med. Chem. 2005, 48, 8079; Wu et al, NucleosidesNucleotides Nuclic Acids 2005, 24, 1543; Choi et al, J. Med. Chem. 2004,47, 2864; Sekiya et al, J. Med. Chem. 2002, 45, 3138; Louie et al,Nucleosides Nucleotides Nuclic Acids 2001, 20, 1099; Serafinowska et al,J. Med. Chem. 1995, 38, 1372; Koh et al, J. Med. Chem. 2005, 48, 2867;Mackman et al, Bioorg. Med. Chem. 2007, 15, 5519; Wang et al,Nucleosides Nucleotides Nuclic Acids 2004, 23, 317; Dyatkina et al,Tetrahedron 1995, 51, 761; Reddy et al, J. Med. Chem. 2008, 51, 666;Krecmerova et al, J. Med. Chem. 2007, 50, 5765.

It will be appreciated that, with appropriate manipulation andprotection of any chemical functionality, synthesis of compounds ofFormula (I) is accomplished by methods analogous to those above and tothose described in the Experimental section. Suitable protecting groupscan be found, but are not restricted to, those found in T W Greene and PG M Wuts “Protective Groups in Organic Synthesis”, 3rd Ed (1999), JWiley and Sons.

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, internet web sites,databases, patents, and patent publications.

Example 1

Compound of Formula (I), wherein R₁═R₃═R₅═R_(5a)═R_(5b)═R_(4a)═H, R₂═OH,B═

Step 1a:

To a mixture of 1,3,5-tri-O-benzoyl-α-D-ribifuranose (23.58 g, 50.99mmol) (1) in dry CH₂Cl₂ (250 mL) was portionwise added Dess-Martinperiodinane (30.8 g, 72.4 mmol) at 0° C. and stirred for 15 min. Then,it was allowed to warm to room temperature and stirred for 17 hrs. Thereaction mixture was evaporated off, triturated with diethyl ether (360mL) and filtered through a fritted funnel. The filtrate was treated withsodium thiosulfate (10 g) and saturated NaHCO₃ aqueous solution (400 mL)and stirred vigorously for 15 min. It was separated and the aqueouslayer was extracted with diethyl ether (100 mL). The combined organiclayer was washed with H₂O and brine, dried over Na₂SO₄, filtered andevaporated to dryness. The residue was azeothropically dried with dryCH₂Cl₂, toluene and hexanes successively to give white foam (2) (22.8g). MS: (ESI-MS) m/z (M+H) 461.12.

Step 1b:

To a mixture of cis-1,2-dichloroethylene (3.8 mL, 50.34 mmol) in drydiethyl ether (80 mL) was dropwise added 1.6M methyllithium in diethylether (31.7 mL, 50.66 mmol) at 0° C. and stirred for 10 min. Thereaction mixture was allowed to warm to room temperature and stirred for105 min. Then, it was cooled to −78° C. and transferred to CeCl₃ (dried,29 g) in dry diethyl ether (pre-cooled at −78° C.) via cannula andstirred at −78° C. for ˜2 hrs before the addition of the product of step1a (2) (7.29 g, 15.83 mmol) in dry diethyl ether (50 mL). The reactionmixture was stirred at −78° C. for 1 hr and quenched by the addition ofsaturated NH₄Cl aqueous solution (200 mL), allowed to warm to roomtemperature, filtered through a pad of celite, washed with saturatedNH₄Cl aqueous solution and methyl tert-butyl ether (200 mL) andseparated. The aqueous layer was extracted with ethyl acetate (200 mL).The combined organic layer was washed with H₂O and brine, dried overNa₂SO₄, filtered and evaporated to give the chloroacetylene adduct as awhite foam (7.625 g), which was directly used for benzoylation withoutpurification. To a mixture of the chloroacetylene adduct (7.62 g, 14.628mmol), DMAP (1.787 g, 14.628 mmol) and triethylamine (12.23 mL, 87.77mL) in dry CH₂Cl₂ (150 mL) was added benzoyl chloride (5.09 mL, 43.88mmol) at 0° C. and stirred for 7 min. Then, it was allowed to warm toroom temperature and stirred for 3 hrs. The reaction was quenched by theaddition of methanol (10 mL), stirred for 10 min, diluted with CH₂Cl₂(200 mL), washed with 1M−HCl, saturated NaHCO₃ aqueous solution andbrine, successively. The organic layer was dried over Na₂SO₄, filteredand evaporated to dryness. The residue was purified by silica gel columnchromatography with 0˜25% ethyl acetate in hexanes to give the compound(3) (7.904 g, α:β=1:3). MS: (ESI) m/z (M+Na) 647.09.

Step 1c:

A mixture of uracil (2.572 g, 22.94 mmol) andN,O-bis(trimethylsilyl)acetamide (11.2 mL, 45.89 mmol) in dryacetonitrile (50 mL) was refluxed for 30 min and cooled to roomtemperature. The product of step 1b (3) in dry acetonitrile (70 mL) wastransferred to previously made bis-silylenolether via cannula. Then,SnCl₄ (5.8 mL, 49.33 mmol) was added to the reaction mixture andrefluxed for 5.5 hrs. After cooling to 0° C., the resction mixture wasdiluted with ethyl acetate (300 mL), slowly treated with cold saturatedNaHCO₃ aqueous solution (350 mL), stirred for 20 min and filteredthrough a pad of celite. The filtrate was separated. The aqueous layerwas extracted with ethyl acetate (2×100 mL). The combined organic layerwas washed with saturated NaHCO₃ aqueous solution and brine,successively. The organic layer was dried over Na₂SO₄, filtered andevaporated to dryness. The residue was purified by silica gel columnchromatography with 0˜60% ethyl acetate in hexanes to give the compound(4) (4.93 g) as a white foam. MS: (ESI) m/z (M+H) 615.04.

Step 1d:

A mixture of the product of step 1c (4) (5.51 g, 8.96 mmol) in 7Nammonia in methanol was stirred at room temperature for 16 hrs andevaporated to dryness. The residue was purified by silica gel columnchromatography with 0˜10% MeOH in CH₂Cl₂ to afford the title compound(2.093 g) as a white foam. MS: (ESI) m/z (M+H) 303.02.

Example 2

Compound of Formula (I), wherein R₁═R₃═R_(5a)═R_(5b)═R_(4a)═H, R₂═OH, B═

R₅═

To a mixture of example 1 (25 mg) and phosphochloridate 5a (5 eq.) indry THF (2˜3 mL) was added 1-methylimidazole (6 eq.) at 0° C., allowedto warm to room temperature and stirred for 15 hrs before the additionof methanol (˜0.2 mL). After evaporation, the residue was passed througha short silica gel column with 0˜6% methanol in CH₂Cl₂. The collectedfraction was evaporated and purified HPLC using 15-90% acetonitrile inwater as a mobile phase. The combined fraction was evaporated in vacuoand lyophilized to afford the title compound of example 2 as a whitesolid. MS: (ESI) m/z (M+H) 650.27.

Example 3

Compound of Formula (I), wherein R₁═R₃═R_(5a)═R_(5b)═R_(4a)═H, R₂═OH, B═

R₅═

The compound of example 3 was prepared by reaction the compound ofexample 1 with compound of (5b) following the same precedure in thepreparation of the compound of example 2. MS: (ESI) m/z (M+H) 594.15.

Example 4

Compound of Formula (I), wherein R₁═R₃═R_(5a)═R_(5b)═R_(4a)═H, R₂═OH, B═

R₅═

The compound of example 4 was prepared by reaction the compound ofexample 1 with compound of (5c) following the same precedure in thepreparation of the compound of example 2. MS: (ESI) m/z (M+H) 636.24.

Example 5

Compound of Formula (I), wherein R₁═R₃═R_(5a)═R_(5b)═R_(4a)═H, R₂═OH, B═

R₅═

The compound of example 5 was prepared by reaction the compound ofexample 1 with compound of (5d) following the same precedure in thepreparation of the compound of example 2. MS: (ESI) m/z (M+H) 670.23.

Example 6

Compound of Formula (I), wherein R₁═R₃═R_(5a)═R_(5b)═R_(4a)═H, R₂═OH, B═

R₅═

The compound of example 6 was prepared by reaction the compound ofexample 1 with compound of (5e) following the same precedure in thepreparation of the compound of example 2. MS: (ESI) m/z (M+H) 650.01.

Example 7

Compound of Formula (I), wherein R₁═R₃═R_(5a)═R_(5b)═R_(4a)═H, R₂═OH, B═

R₅═

The compound of example 7 was prepared by reaction the compound ofexample 1 with compound of (5f) following the same precedure in thepreparation of the compound of example 2. MS: (ESI) m/z (M+H) 622.27.

Example 8

Compound of Formula (I), wherein R₁═R₃═R_(5a)═R_(5b)═R_(4a)═H, R₂═OH, B═

R₅═

The compound of example 8 was prepared by reaction the compound ofexample 1 with compound of (5 g) following the same precedure in thepreparation of the compound of example 2. MS: (ESI) m/z (M+H) 648.26.

Example 9

Compound of Formula (I), wherein R₁═R₃═R_(5a)═R_(5b)═R_(4a)═H, R₂═OH, B═

R₅═

The compound of example 9 was prepared by reaction the compound ofexample 1 with compound of (5h) following the same precedure in thepreparation of the compound of example 2. MS: (ESI) m/z (M+H) 662.28.

Biological Activity

1. HCV Replicon Cell Lines

HCV replicon cell lines (kindly provided by R. Bartenschlager) isolatedfrom colonies as described by Lohman et al. (Lohman et al. (1999)Science 285: 110-113, expressly incorporated by reference in itsentirety) and used for all experiments. One of the HCV replicon celllines (strain Conl, genotype 1b) has the nucleic acid sequence set forthin EMBL Accession No.: AJ242651, the coding sequence of which is fromnucleotides 1801 to 8406. Another replicon cell line (strain H77,genotype 1a) was constructed as described by Yi et. al. (Yi et. al.(2004) Journal of Virology 78(15):7904-15). The coding sequences of thepublished HCV replicons were synthesized and subsequently assembled inplasmids using standard molecular biology techniques.

One replicon cell line (“SGR 11-7”) stably expresses HCV replicon RNA,genotype 1b, which consists of (i) the HCV 5′UTR fused to the first 12amino acids of the capsid protein, (ii) the neomycin phosphotransferasegene (neo), (iii) the IRES from encephalomyocarditis virus (EMCV) and(iv) HCV NS2 to NS5B genes and the HCV 3′UTR. Another replicon cell line(“Huh-1a7”) described by Yi et. al. (Yi et. al. (2004) Journal ofVirology 78(15):7904-15, expressly incorporated by reference in itsentirety) stably expresses HCV replicon RNA, genotype 1a, which consistsof (i) the HCV 5′UTR fused to the first 12 amino acids of the capsidprotein, (ii) the HIV tat protein, (iii) the neomycin phosphotransferasegene (neo), (iv) the IRES from encephalomyocarditis virus (EMCV) and(vi) HCV NS3 to NS5B genes that harbor cell culture adaptive mutations(Q1067R, K1691R, S2204I) and the HCV 3′UTR.

These cell lines are maintained at 37° C., 5% CO₂, 100% relativehumidity in DMEM (Cat#11965-084, Invitrogen), with 10% fetal calf serum(“FCS”, Invitrogen), 1% non-essential amino acids (Invitrogen), 1% ofGlutamax (Invitrogen), 1% of 100× penicillin/streptomycin(Cat#15140-122, Invitrogen) and Geneticin (Cat#10131-027, Invitrogen) at0.75 mg/ml or 0.25 mg/ml for 11-7 and Huh-1a7 cells, respectively.

2. HCV Replicon Assay—qRT-PCR.

EC₅₀ values of single agent compounds were determined by HCV RNAdetection using quantitative RT-PCR, according to the manufacturer'sinstructions, with a TAQMAN® One-Step RT-PCR Master Mix Reagents Kit(Cat#AB 4309169, Applied Biosystems) on an ABI Model 7500 thermocycler.EC₅₀ values of combinations are similarly determined by HCV RNAdetection using quantitative RT-PCR. The TAQMAN primers to use fordetecting and quantifying HCV RNA obtained from Integrated DNATechnologies. HCV RNA is normalized to GAPDH RNA levels in drug-treatedcells, which is detected and quantified using the Human GAPDH EndogenousControl Mix (Applied Biosystems, AB 4310884E). Total cellular RNA ispurified from 96-well plates using the RNAqueous 96 kit (Ambion,Cat#AM1812). Chemical agent cytotoxicity is evaluated using an MTS assayaccording to the manufacturer's directions (Promega).

The compounds of the present invention can be effective against the HCV1a and 1b genotypes. It should also be understood that the compounds ofthe present invention can inhibit multiple genotypes of HCV. In oneembodiment, compounds of the present invention are active against the1a, 1b, 2a, 2b, 3a, 4a, and 5a genotypes. Table 6 shows the EC₅₀ valuesof representative compounds of the present invention against the HCV 1aand 1b genotypes from the above described qRT-PCR. EC₅₀ ranges againstHCV 1a or 1b are as follows: A>1 μM; B 0.1-1 μM; C<0.1 μM.

TABLE 6 Genotype-1a or 1b replicon EC₅₀ Example Structures 1a EC₅₀ 1bEC₅₀ 1

A A 2

B B 3

B B 4

C C 5

B B 6

B B 7

B B 8

B A 9

B B 10

A  A.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A compound represented by Formula (I):

or the β-L enantiomer thereof, or a pharmaceutically acceptable salt,ester, stereoisomer, tautomer, solvate, or combination thereof, wherein:R₁ is selected from the group consisting of: 1) hydrogen; 2) —N; 3)halogen; 4) —N₃; and 5) Substituted or unsubstituted —C₁-C₈ alkyl; R₂ isselected from the group consisting of: 1) halogen; 2) —CN; 3) —N₃; and4) OR₆; where R₆ is selected from the group consisting of: hydrogen,hydroxy protecting group, —C(O)R₇, —C(O)OR₇, and —C(O)NR_(8a)R_(8b);wherein R₇ is selected from the group consisting of: substituted orunsubstituted —C₁-C₈ alkyl, substituted or unsubstituted —C₂-C₈ alkenyl,substituted or unsubstituted —C₂-C₈ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, andsubstituted or unsubstituted heterocyclic; R_(8a) and R_(8b) are eachindependently selected from the group consisting of: hydrogen and R₇; oralternatively R_(8a) and R_(8b) taken together with the nitrogen atom towhich they are attached form a heterocyclic ring; R_(4a) is selectedfrom the group consisting of: 1) halogen; 2) hydrogen; 3) —CN; 4) —N₃;and 5) OR₆; R₃ is R₆; or alternatively R₂ is —OR₆ and R₃ and R₆ togetherform a group selected from: —C(Me)₂-, —C(CH₂)₄—, —CH(Ph)-, —CH(OMe)- and—P(O)(OH)—; B is selected from the group consisting of: substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, andsubstituted or unsubstituted heterocyclic; R_(5a) and R_(5b) areindependently selected from the group consisting of: 1) hydrogen; 2)substituted or unsubstituted —C₁-C₈ alkyl; 3) substituted orunsubstituted —C₂-C₈ alkenyl; 4) substituted or unsubstituted —C₂-C₈alkynyl; 5) or R_(5a) and R_(5b) are taken together with the carbon atomto which they are attached to form a group selected from —C₃-C₈cycloalkyl, —C₃-C₈ cycloalkenyl, or —C₃-C₈ cycloalkynyl; R₅ is selectedfrom the group consisting of: 1) hydrogen; 2) R₆; 3)—P(O)(OR_(7a))(OR_(7b)); wherein R_(7a) and R_(7b) are eachindependently selected from the group consisting of a) hydrogen; b)unsubstituted or substituted —C₁-C₈ alkyl; 4)—P(O)(OR_(7a))—O—P(O)(OR_(7b))(OR_(7c)); wherein R_(7a) and R_(7b) arepreviously defined; R_(7c) is selected from the group consisting of a)hydrogen; b) unsubstituted or substituted —C₁-C₈ alkyl; 5)—P(O)(OR_(7a))—O—P(O)(OR_(7b))—O—P(O)(OR_(7c))(OR_(7d)); wherein R_(7a),R_(7b) and R_(7c) are previously defined; R_(7d) is selected from thegroup consisting of a) hydrogen; b) unsubstituted or substituted —C₁-C₈alkyl; 6)

where X is O or S; R₉ is R₇ wherein R₇ is previously defined; R₁₀, R₁₁and R₁₂ are each independently selected from the group consisting of: a)hydrogen; and b) unsubstituted or substituted —C₁-C₈ alkyl; or R₁₁ ishydrogen, and R₁₂ and R₁₀ taken together with the nitrogen which R₁₀ isattached to form a heterocyclic ring; or R₁₁ and R₁₂ taken together withthe carbon which they are attached form a ring; R₁₃ is hydrogen or R₇,wherein R₇ is previously defined; and 7)

where X is O or S; n is 1-4; R_(8a) and R_(8b) are as previouslydefined; R₁₄ is hydrogen or —(CO)—R₇, wherein R₇ is as previouslydefined; Or, R₅ and R₃ are taken together to form

where X is O or S; and R₆ is as previously defined.
 2. A compound ofclaim 1 represented by Formula (II):

or its β-L enantiomer, or a pharmaceutically acceptable salt, ester,stereoisomer, tautomer, solvate, or combination thereof.
 3. A compoundof claim 1 represented by Formula (III):

or its β-L enantiomer, or a pharmaceutically acceptable salt, ester,stereoisomer, tautomer, solvate, or combination thereof.
 4. A compoundof claim 1 represented by Formula (IV):

or its β-L enantiomer, or a pharmaceutically acceptable salt, ester,stereoisomer, tautomer, solvate, or combination thereof.
 5. A compoundof claim 1 represented by Formula (V):

or its β-L enantiomer, or a pharmaceutically acceptable salt, ester,stereoisomer, tautomer, solvate, or combination thereof.
 6. A compoundof claim 1 represented by Formula (VI):

or its β-L enantiomer, or a pharmaceutically acceptable salt, ester,stereoisomer, tautomer, solvate, or combination thereof.
 7. The compoundof claim 1, wherein B is represented by formula (B1) or (B2):

wherein: Y is selected from the group consisting of: O, S, NR_(8a),NC(O)R₇, NC(O)OR₇ and NC(O)NR_(8a)R_(8b); T, U, V and W are eachindependently N or CR₁₈; wherein R₁₈ is selected from the groupconsisting of: hydrogen, halogen, —CN, —C(O)R₇, —C(O)NR_(8a)R_(8b),—NO₂, —N₃, —OR₇, —SR₇, —NR_(8a)R_(8b), —OC(O)R₇, —OC(O)OR₇, —NHC(O)R₇,—NHC(O)OR₇ and —NHC(O)NR_(8a)R_(8b), substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocyclic, substituted or unsubstituted —C₁-C₈ alkyl, substituted orunsubstituted —C₂-C₈ alkenyl, and substituted or unsubstituted —C₂-C₈alkynyl; R₁₅, R₁₆ and R₁₇ are each independently selected from the groupconsisting of: hydrogen, halogen, —CN, —C(O)R₇, —C(O)NR_(8a)R_(8b),—NO₂, —N₃, —OR₇, —SR₇, —NR_(8a)R_(8b), —OC(O)R₇, —OC(O)OR₇, —NHC(O)R₇,—NHC(O)OR₇ and —NHC(O)NR_(8a)R_(8b), substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocyclic, substituted or unsubstituted —C₁-C₈ alkyl, substituted orunsubstituted —C₂-C₈ alkenyl, and substituted or unsubstituted —C₂-C₈alkynyl.
 8. A compound according to claim 1 as set forth in any ofTables 1˜Table 5 which is selected from: (a) Compounds of Formula (II-1)wherein R₂, R_(4a), R_(5a), R_(5b), and B are delineated for eachcompound in Table 1 TABLE 1 (II-1)

Compound R_(5a) R_(5b) R_(4a) R₂ B 1 H H H OH

2 H H H F

3 H H N₃ OH

4 H H N₃ F

5 H Me H OH

6 H Me H F

7 Me H H OH

8 Me H H F

9 H H H OH

10 H H H F

11 H H N₃ OH

12 H H N₃ F

13 H Me H OH

14 H Me H F

15 Me H H OH

16 Me H H F

17 H H H OH

18 H H H F

19 H H N₃ OH

20 H H N₃ F

21 H Me H OH

22 H Me H F

23 Me H H OH

24 Me H H F

25 H H H OH

26 H H H F

27 H H N₃ OH

28 H H N₃ F

29 H Me H OH

30 H Me H F

31 Me H H OH

32 Me H H F

33 H H H OH

34 H H H F

35 H H N₃ OH

36 H H N₃ F

37 H Me H OH

38 H Me H F

39 Me H H OH

40 Me H H F

41 H H H OH

42 H H H F

43 H H N₃ OH

44 H H N₃ F

45 H Me H OH

46 H Me H F

47 Me H H OH

48 Me H H F

49 H H H OH

50 H H H F

51 H H N₃ OH

52 H H N₃ F

53 H Me H OH

54 H Me H F

55 Me H H OH

56 Me H H F

57 H H H OH

58 H H H F

59 H H N₃ OH

60 H H N₃ F

61 H Me H OH

62 H Me H F

63 Me H H OH

64 Me H H F

65 H H H OH

66 H H H F

67 H H N₃ OH

68 H H N₃ F

69 H Me H OH

70 H Me H F

71 Me H H OH

72 Me H H F

73 H H H OH

74 H H H F

75 H H N₃ OH

76 H H N₃ F

77 H Me H OH

78 H Me H F

79 Me H H OH

80 Me H H F

(b) compounds of Formula (III-1) wherein R₂, R₇, R_(5a), R_(5b), and Bare delineated for each compound in Table 2 TABLE 2 (III-1)

Compound R_(5a) R_(5b) R₂ R₇ B  81 H H OH i-Pr

 82 H H F i-Pr

 83 H Me OH i-Pr

 84 H Me F i-Pr

 85 Me H OH i-Pr

 86 Me H F i-Pr

 87 H H OH i-Pr

 88 H H F i-Pr

 89 H Me OH i-Pr

 90 H Me F i-Pr

 91 Me H OH i-Pr

 92 Me H F i-Pr

 93 H H OH i-Pr

 94 H H F i-Pr

 95 H Me OH i-Pr

 96 H Me F i-Pr

 97 Me H OH i-Pr

 98 Me H F i-Pr

 99 H H OH i-Pr

100 H H F i-Pr

101 H Me OH i-Pr

101a H Me F i-Pr

102 Me H OH i-Pr

103 Me H F i-Pr

104 H H OH i-Pr

105 H H F i-Pr

106 H Me OH i-Pr

107 H Me F i-Pr

108 Me H OH i-Pr

109 Me H F i-Pr

110 H H OH i-Pr

111 H H F i-Pr

112 H Me OH i-Pr

113 H Me F i-Pr

114 Me H OH i-Pr

115 Me H F i-Pr

116 H H OH i-Pr

117 H H F i-Pr

118 H Me OH i-Pr

119 H Me F i-Pr

120 Me H OH i-Pr

121 Me H F i-Pr

122 H H OH i-Pr

123 H H F i-Pr

124 H Me OH i-Pr

125 H Me F i-Pr

126 Me H OH i-Pr

127 Me H F i-Pr

128 H H OH i-Pr

129 H H F i-Pr

130 H Me OH i-Pr

131 H Me F i-Pr

132 Me H OH i-Pr

133 Me H F i-Pr

134 H H OH i-Pr

135 H H F i-Pr

136 H Me OH i-Pr

137 H Me F i-Pr

138 Me H OH i-Pr

139 Me H F i-Pr

140 H H OH Et

141 H H F Et

142 H Me OH Et

143 H Me F Et

144 Me H OH Et

145 Me H F Et

146 H H OH Et

147 H H F Et

148 H Me OH Et

149 H Me F Et

150 Me H OH Et

151 Me H F Et

152 H H OH Et

153 H H F Et

154 H Me OH Et

155 H Me F Et

156 Me H OH Et

157 Me H F Et

158 H H OH Et

159 H H F Et

160 H Me OH Et

161 H Me F Et

162 Me H OH Et

163 Me H F Et

164 H H OH Et

165 H H F Et

166 H Me OH Et

167 H Me F Et

168 Me H OH Et

169 Me H F Et

170 H H OH Et

171 H H F Et

172 H Me OH Et

173 H Me F Et

174 Me H OH Et

175 Me H F Et

176 H H OH Et

177 H H F Et

178 H Me OH Et

179 H Me F Et

180 Me H OH Et

181 Me H F Et

182 H H OH Et

183 H H F Et

184 H Me OH Et

185 H Me F Et

186 Me H OH Et

187 Me H F Et

188 H H OH Et

189 H H F Et

190 H Me OH Et

191 H Me F Et

192 Me H OH Et

193 Me H F Et

194 H H OH Et

195 H H F Et

196 H Me OH Et

197 H Me F Et

198 Me H OH Et

199 Me H F Et

200 H H OH i-Bu

201 H H F i-Bu

202 H Me OH i-Bu

203 H Me F i-Bu

204 Me H OH i-Bu

205 Me H F i-Bu

206 H H OH i-Bu

207 H H F i-Bu

208 H Me OH i-Bu

209 H Me F i-Bu

210 Me H OH i-Bu

211 Me H F i-Bu

212 H H OH i-Bu

213 H H F i-Bu

214 H Me OH i-Bu

215 H Me F i-Bu

216 Me H OH i-Bu

217 Me H F i-Bu

218 H H OH i-Bu

219 H H F i-Bu

220 H Me OH i-Bu

221 H Me F i-Bu

222 Me H OH i-Bu

223 Me H F i-Bu

224 H H OH i-Bu

225 H H F i-Bu

226 H Me OH i-Bu

227 H Me F i-Bu

228 Me H OH i-Bu

229 Me H F i-Bu

230 H H OH i-Bu

231 H H F i-Bu

232 H Me OH i-Bu

233 H Me F i-Bu

234 Me H OH i-Bu

235 Me H F i-Bu

236 H H OH i-Bu

237 H H F i-Bu

238 H Me OH i-Bu

239 H Me F i-Bu

240 Me H OH i-Bu

241 Me H F i-Bu

242 H H OH i-Bu

243 H H F i-Bu

244 H Me OH i-Bu

245 H Me F i-Bu

246 Me H OH i-Bu

247 Me H F i-Bu

248 H H OH i-Bu

249 H H F i-Bu

250 H Me OH i-Bu

251 H Me F i-Bu

252 Me H OH i-Bu

253 Me H F i-Bu

254 H H OH i-Bu

255 H H F i-Bu

256 H Me OH i-Bu

257 H Me F i-Bu

259 Me H OH i-Bu

260 Me H F i-Bu

(c) compounds of Formula (IV-1) wherein R₂, R₉, R₁₂, R₁₃, and B aredelineated for each compound in Table 3 TABLE 3 (IV-1)

Com- pound R₂ R₉ R₁₂ R₁₃ B 261 OH Ph Me Me

262 F Ph Me Me

263 OH Ph Me Me

264 F Ph Me Me

265 OH Ph Me Me

266 F Ph Me Me

267 OH Ph Me Me

268 F Ph Me Me

269 OH Ph Me Me

270 F Ph Me Me

271 OH Ph Me Me

272 F Ph Me Me

273 OH Ph Me Me

274 F Ph Me Me

275 OH Ph Me Me

276 F Ph Me Me

277 OH Ph Me Me

278 F Ph Me Me

279 OH Ph Me Me

280 F Ph Me Me

281 OH 1-Naphthyl Me Me

282 F 1-Naphthyl Me Me

283 OH 1-Naphthyl Me Me

284 F 1-Naphthyl Me Me

285 OH 1-Naphthyl Me Me

286 F 1-Naphthyl Me Me

287 OH 1-Naphthyl Me Me

288 F 1-Naphthyl Me Me

289 OH 1-Naphthyl Me Me

290 F 1-Naphthyl Me Me

291 OH 1-Naphthyl Me Me

292 F 1-Naphthyl Me Me

293 OH 1-Naphthyl Me Me

294 F 1-Naphthyl Me Me

295 OH 1-Naphthyl Me Me

296 F 1-Naphthyl Me Me

297 OH 1-Naphthyl Me Me

298 F 1-Naphthyl Me Me

299 OH 1-Naphthyl Me Me

300 F 1-Naphthyl Me Me

301 OH Ph H Me

302 F Ph H Me

303 OH Ph H Me

304 F Ph H Me

305 OH Ph H Me

306 F Ph H Me

307 OH Ph H Me

308 F Ph H Me

309 OH Ph H Me

310 F Ph H Me

311 OH Ph H Me

312 F Ph H Me

313 OH Ph H Me

314 F Ph H Me

315 OH Ph H Me

316 F Ph H Me

317 OH Ph H Me

318 F Ph H Me

319 OH Ph H Me

320 F Ph H Me

321 OH 1-Naphthyl H Me

322 F 1-Naphthyl H Me

323 OH 1-Naphthyl H Me

324 F 1-Naphthyl H Me

325 OH 1-Naphthyl H Me

326 F 1-Naphthyl H Me

327 OH 1-Naphthyl H Me

328 F 1-Naphthyl H Me

329 OH 1-Naphthyl H Me

330 F 1-Naphthyl H Me

331 OH 1-Naphthyl H Me

332 F 1-Naphthyl H Me

333 OH 1-Naphthyl H Me

334 F 1-Naphthyl H Me

335 OH 1-Naphthyl H Me

336 F 1-Naphthyl H Me

337 OH 1-Naphthyl H Me

338 F 1-Naphthyl H Me

339 OH 1-Naphthyl H Me

340 F 1-Naphthyl H Me

341 OH Ph Me n-Pentyl

342 F Ph Me n-Pentyl

343 OH Ph Me n-Pentyl

344 F Ph Me n-Pentyl

345 OH Ph Me n-Pentyl

346 F Ph Me n-Pentyl

347 OH Ph Me n-Pentyl

348 F Ph Me n-Pentyl

349 OH Ph Me n-Pentyl

350 F Ph Me n-Pentyl

351 OH Ph Me n-Pentyl

352 F Ph Me n-Pentyl

353 OH Ph Me n-Pentyl

354 F Ph Me n-Pentyl

355 OH Ph Me n-Pentyl

356 F Ph Me n-Pentyl

357 OH Ph Me n-Pentyl

358 F Ph Me n-Pentyl

359 OH Ph Me n-Pentyl

360 F Ph Me n-Pentyl

361 OH 1-Naphthyl Me n-Pentyl

362 F 1-Naphthyl Me n-Pentyl

363 OH 1-Naphthyl Me n-Pentyl

364 F 1-Naphthyl Me n-Pentyl

365 OH 1-Naphthyl Me n-Pentyl

366 F 1-Naphthyl Me n-Pentyl

367 OH 1-Naphthyl Me n-Pentyl

368 F 1-Naphthyl Me n-Pentyl

369 OH 1-Naphthyl Me n-Pentyl

370 F 1-Naphthyl Me n-Pentyl

371 OH 1-Naphthyl Me n-Pentyl

372 F 1-Naphthyl Me n-Pentyl

373 OH 1-Naphthyl Me n-Pentyl

374 F 1-Naphthyl Me n-Pentyl

375 OH 1-Naphthyl Me n-Pentyl

376 F 1-Naphthyl Me n-Pentyl

377 OH 1-Naphthyl Me n-Pentyl

378 F 1-Naphthyl Me n-Pentyl

379 OH 1-Naphthyl Me n-Pentyl

380 F 1-Naphthyl Me n-Pentyl

381 OH Ph H n-Pentyl

382 F Ph H n-Pentyl

383 OH Ph H n-Pentyl

384 F Ph H n-Pentyl

385 OH Ph H n-Pentyl

386 F Ph H n-Pentyl

387 OH Ph H n-Pentyl

388 F Ph H n-Pentyl

389 OH Ph H n-Pentyl

390 F Ph H n-Pentyl

391 OH Ph H n-Pentyl

392 F Ph H n-Pentyl

393 OH Ph H n-Pentyl

394 F Ph H n-Pentyl

395 OH Ph H n-Pentyl

396 F Ph H n-Pentyl

397 OH Ph H n-Pentyl

398 F Ph H n-Pentyl

399 OH Ph H n-Pentyl

400 F Ph H n-Pentyl

401 OH 1-Naphthyl H n-Pentyl

402 F 1-Naphthyl H n-Pentyl

403 OH 1-Naphthyl H n-Pentyl

404 F 1-Naphthyl H n-Pentyl

405 OH 1-Naphthyl H n-Pentyl

406 F 1-Naphthyl H n-Pentyl

407 OH 1-Naphthyl H n-Pentyl

408 F 1-Naphthyl H n-Pentyl

409 OH 1-Naphthyl H n-Pentyl

410 F 1-Naphthyl H n-Pentyl

411 OH 1-Naphthyl H n-Pentyl

412 F 1-Naphthyl H n-Pentyl

413 OH 1-Naphthyl H n-Pentyl

414 F 1-Naphthyl H n-Pentyl

415 OH 1-Naphthyl H n-Pentyl

416 F 1-Naphthyl H n-Pentyl

417 OH 1-Naphthyl H n-Pentyl

418 F 1-Naphthyl H n-Pentyl

419 OH 1-Naphthyl H n-Pentyl

420 F 1-Naphthyl H n-Pentyl

421 OH Ph Me i-Pr

422 F Ph Me i-Pr

423 OH Ph Me i-Pr

424 F Ph Me i-Pr

425 OH Ph Me i-Pr

426 F Ph Me i-Pr

427 OH Ph Me i-Pr

428 F Ph Me i-Pr

429 OH Ph Me i-Pr

430 F Ph Me i-Pr

431 OH Ph Me i-Pr

432 F Ph Me i-Pr

433 OH Ph Me i-Pr

434 F Ph Me i-Pr

435 OH Ph Me i-Pr

436 F Ph Me i-Pr

437 OH Ph Me i-Pr

438 F Ph Me i-Pr

439 OH Ph Me i-Pr

440 F Ph Me i-Pr

441 OH 1-Naphthyl Me i-Pr

442 F 1-Naphthyl Me i-Pr

443 OH 1-Naphthyl Me i-Pr

444 F 1-Naphthyl Me i-Pr

445 OH 1-Naphthyl Me i-Pr

446 F 1-Naphthyl Me i-Pr

447 OH 1-Naphthyl Me i-Pr

448 F 1-Naphthyl Me i-Pr

449 OH 1-Naphthyl Me i-Pr

450 F 1-Naphthyl Me i-Pr

451 OH 1-Naphthyl Me i-Pr

452 F 1-Naphthyl Me i-Pr

453 OH 1-Naphthyl Me i-Pr

454 F 1-Naphthyl Me i-Pr

455 OH 1-Naphthyl Me i-Pr

456 F 1-Naphthyl Me i-Pr

457 OH 1-Naphthyl Me i-Pr

458 F 1-Naphthyl Me i-Pr

459 OH 1-Naphthyl Me i-Pr

460 F 1-Naphthyl Me i-Pr

461 OH Ph H i-Pr

462 F Ph H i-Pr

463 OH Ph H i-Pr

464 F Ph H i-Pr

465 OH Ph H i-Pr

466 F Ph H i-Pr

467 OH Ph H i-Pr

468 F Ph H i-Pr

469 OH Ph H i-Pr

470 F Ph H i-Pr

471 OH Ph H i-Pr

472 F Ph H i-Pr

473 OH Ph H i-Pr

474 F Ph H i-Pr

475 OH Ph H i-Pr

476 F Ph H i-Pr

477 OH Ph H i-Pr

478 F Ph H i-Pr

479 OH Ph H i-Pr

480 F Ph H i-Pr

481 OH 1-Naphthyl H i-Pr

482 F 1-Naphthyl H i-Pr

483 OH 1-Naphthyl H i-Pr

484 F 1-Naphthyl H i-Pr

485 OH 1-Naphthyl H i-Pr

486 F 1-Naphthyl H i-Pr

487 OH 1-Naphthyl H i-Pr

488 F 1-Naphthyl H i-Pr

489 OH 1-Naphthyl H i-Pr

490 F 1-Naphthyl H i-Pr

491 OH 1-Naphthyl H i-Pr

492 F 1-Naphthyl H i-Pr

493 OH 1-Naphthyl H i-Pr

494 F 1-Naphthyl H i-Pr

495 OH 1-Naphthyl H i-Pr

496 F 1-Naphthyl H i-Pr

497 OH 1-Naphthyl H i-Pr

498 F 1-Naphthyl H i-Pr

499 OH 1-Naphthyl H i-Pr

500 F 1-Naphthyl H i-Pr

501 OH Ph Me Benzyl

502 F Ph Me Benzyl

503 OH Ph Me Benzyl

504 F Ph Me Benzyl

505 OH Ph Me Benzyl

506 F Ph Me Benzyl

507 OH Ph Me Benzyl

508 F Ph Me Benzyl

509 OH Ph Me Benzyl

510 F Ph Me Benzyl

511 OH Ph Me Benzyl

512 F Ph Me Benzyl

513 OH Ph Me Benzyl

514 F Ph Me Benzyl

515 OH Ph Me Benzyl

516 F Ph Me Benzyl

517 OH Ph Me Benzyl

518 F Ph Me Benzyl

519 OH Ph Me Benzyl

520 F Ph Me Benzyl

521 OH 1-Naphthyl Me Benzyl

522 F 1-Naphthyl Me Benzyl

523 OH 1-Naphthyl Me Benzyl

524 F 1-Naphthyl Me Benzyl

525 OH 1-Naphthyl Me Benzyl

526 F 1-Naphthyl Me Benzyl

527 OH 1-Naphthyl Me Benzyl

528 F 1-Naphthyl Me Benzyl

529 OH 1-Naphthyl Me Benzyl

530 F 1-Naphthyl Me Benzyl

531 OH 1-Naphthyl Me Benzyl

532 F 1-Naphthyl Me Benzyl

533 OH 1-Naphthyl Me Benzyl

534 F 1-Naphthyl Me Benzyl

535 OH 1-Naphthyl Me Benzyl

536 F 1-Naphthyl Me Benzyl

537 OH 1-Naphthyl Me Benzyl

538 F 1-Naphthyl Me Benzyl

539 OH 1-Naphthyl Me Benzyl

540 F 1-Naphthyl Me Benzyl

541 OH Ph H Benzyl

542 F Ph H Benzyl

543 OH Ph H Benzyl

544 F Ph H Benzyl

545 OH Ph H Benzyl

546 F Ph H Benzyl

547 OH Ph H Benzyl

548 F Ph H Benzyl

549 OH Ph H Benzyl

550 F Ph H Benzyl

551 OH Ph H Benzyl

552 F Ph H Benzyl

553 OH Ph H Benzyl

554 F Ph H Benzyl

555 OH Ph H Benzyl

556 F Ph H Benzyl

557 OH Ph H Benzyl

558 F Ph H Benzyl

559 OH Ph H Benzyl

560 F Ph H Benzyl

561 OH 1-Naphthyl H Benzyl

562 F 1-Naphthyl H Benzyl

563 OH 1-Naphthyl H Benzyl

564 F 1-Naphthyl H Benzyl

565 OH 1-Naphthyl H Benzyl

566 F 1-Naphthyl H Benzyl

567 OH 1-Naphthyl H Benzyl

568 F 1-Naphthyl H Benzyl

569 OH 1-Naphthyl H Benzyl

570 F 1-Naphthyl H Benzyl

571 OH 1-Naphthyl H Benzyl

572 F 1-Naphthyl H Benzyl

573 OH 1-Naphthyl H Benzyl

574 F 1-Naphthyl H Benzyl

575 OH 1-Naphthyl H Benzyl

576 F 1-Naphthyl H Benzyl

577 OH 1-Naphthyl H Benzyl

578 F 1-Naphthyl H Benzyl

579 OH 1-Naphthyl H Benzyl

580 F 1-Naphthyl H Benzyl

581 OH Ph Me t-BuCH₂—

582 F Ph Me t-BuCH₂—

583 OH Ph Me t-BuCH₂—

584 F Ph Me t-BuCH₂—

585 OH Ph Me t-BuCH₂—

586 F Ph Me t-BuCH₂—

587 OH Ph Me t-BuCH₂—

588 F Ph Me t-BuCH₂—

589 OH Ph Me t-BuCH₂—

590 F Ph Me t-BuCH₂—

591 OH Ph Me t-BuCH₂—

592 F Ph Me t-BuCH₂—

593 OH Ph Me t-BuCH₂—

594 F Ph Me t-BuCH₂—

595 OH Ph Me t-BuCH₂—

596 F Ph Me t-BuCH₂—

597 OH Ph Me t-BuCH₂—

598 F Ph Me t-BuCH₂—

599 OH Ph Me t-BuCH₂—

600 F Ph Me t-BuCH₂—

601 OH 1-Naphthyl Me t-BuCH₂—

602 F 1-Naphthyl Me t-BuCH₂—

603 OH 1-Naphthyl Me t-BuCH₂—

604 F 1-Naphthyl Me t-BuCH₂—

605 OH 1-Naphthyl Me t-BuCH₂—

606 F 1-Naphthyl Me t-BuCH₂—

607 OH 1-Naphthyl Me t-BuCH₂—

608 F 1-Naphthyl Me t-BuCH₂—

609 OH 1-Naphthyl Me t-BuCH₂—

610 F 1-Naphthyl Me t-BuCH₂—

611 OH 1-Naphthyl Me t-BuCH₂—

612 F 1-Naphthyl Me t-BuCH₂—

613 OH 1-Naphthyl Me t-BuCH₂—

614 F 1-Naphthyl Me t-BuCH₂—

615 OH 1-Naphthyl Me t-BuCH₂—

616 F 1-Naphthyl Me t-BuCH₂—

617 OH 1-Naphthyl Me t-BuCH₂—

618 F 1-Naphthyl Me t-BuCH₂—

619 OH 1-Naphthyl Me t-BuCH₂—

620 F 1-Naphthyl Me t-BuCH₂—

621 OH Ph H t-BuCH₂—

622 F Ph H t-BuCH₂—

623 OH Ph H t-BuCH₂—

624 F Ph H t-BuCH₂—

625 OH Ph H t-BuCH₂—

626 F Ph H t-BuCH₂—

627 OH Ph H t-BuCH₂—

628 F Ph H t-BuCH₂—

629 OH Ph H t-BuCH₂—

630 F Ph H t-BuCH₂—

631 OH Ph H t-BuCH₂—

632 F Ph H t-BuCH₂—

633 OH Ph H t-BuCH₂—

634 F Ph H t-BuCH₂—

635 OH Ph H t-BuCH₂—

636 F Ph H t-BuCH₂—

637 OH Ph H t-BuCH₂—

638 F Ph H t-BuCH₂—

639 OH Ph H t-BuCH₂—

640 F Ph H t-BuCH₂—

641 OH 1-Naphthyl H t-BuCH₂—

642 F 1-Naphthyl H t-BuCH₂—

643 OH 1-Naphthyl H t-BuCH₂—

644 F 1-Naphthyl H t-BuCH₂—

645 OH 1-Naphthyl H t-BuCH₂—

646 F 1-Naphthyl H t-BuCH₂—

647 OH 1-Naphthyl H t-BuCH₂—

648 F 1-Naphthyl H t-BuCH₂—

649 OH 1-Naphthyl H t-BuCH₂—

650 F 1-Naphthyl H t-BuCH₂—

651 OH 1-Naphthyl H t-BuCH₂—

652 F 1-Naphthyl H t-BuCH₂—

653 OH 1-Naphthyl H t-BuCH₂—

654 F 1-Naphthyl H t-BuCH₂—

655 OH 1-Naphthyl H t-BuCH₂—

656 F 1-Naphthyl H t-BuCH₂—

657 OH 1-Naphthyl H t-BuCH₂—

658 F 1-Naphthyl H t-BuCH₂—

659 OH 1-Naphthyl H t-BuCH₂—

660 F 1-Naphthyl H t-BuCH₂—

(d) compounds of Formula (V-1) wherein R₂, R_(8a), R_(8b), R₁₄, and Bare delineated for each compound in Table 4 TABLE 4 (V-1)

Compound R₂ R₁₄ NR_(8a)R_(8b) B 661 OH

662 F

663 OH

664 F

665 OH

666 F

667 OH

668 F

669 OH

670 F

671 OH

672 F

673 OH

674 F

675 OH

676 F

677 OH

678 F

679 OH

680 F

681 OH

682 F

683 OH

684 F

685 OH

686 F

687 OH

688 F

689 OH

690 F

691 OH

692 F

693 OH

694 F

695 OH

696 F

697 OH

698 F

699 OH

700 F

701 OH

702 F

703 OH

704 F

705 OH

706 F

707 OH

708 F

709 OH

710 F

711 OH

712 F

713 OH

714 F

715 OH

716 F

717 OH

718 F

719 OH

720 F

721 OH

722 F

723 OH

724 F

725 OH

726 F

727 OH

728 F

729 OH

730 F

731 OH

732 F

733 OH

734 F

735 OH

736 F

737 OH

738 F

739 OH

740 F

741 OH

742 F

743 OH

744 F

745 OH

746 F

747 OH

748 F

749 OH

750 F

751 OH

752 F

753 OH

754 F

755 OH

756 F

757 OH

758 F

759 OH

760 F

761 OH

762 F

763 OH

764 F

765 OH

766 F

767 OH

768 F

769 OH

770 F

771 OH

772 F

773 OH

774 F

775 OH

776 F

777 OH

778 F

779 OH

780 F

781 OH

782 F

783 OH

784 F

785 OH

786 F

787 OH

788 F

789 OH

790 F

791 OH

792 F

793 OH

794 F

795 OH

796 F

797 OH

798 F

799 OH

800 F

801 OH

802 F

803 OH

804 F

805 OH

806 F

807 OH

808 F

809 OH

810 F

811 OH

812 F

813 OH

814 F

815 OH

816 F

817 OH

818 F

819 OH

820 F

and (e) compounds of Formula (VI-1) wherein R₂, R_(5a), R_(5b), R₆, andB are delineated for each compound in Table 5 TABLE 5 (VI-1)

Compound R₆ R_(5a) R_(5b) R₂ B 821 i-Pr H H OH

822 i-Pr H H F

823 i-Pr H Me OH

824 i-Pr H Me F

825 i-Pr Me H OH

826 i-Pr Me H F

827 i-Pr H H OH

828 i-Pr H H F

829 i-Pr H Me OH

830 i-Pr H Me F

831 i-Pr Me H OH

832 i-Pr Me H F

833 i-Pr H H OH

834 i-Pr H H F

835 i-Pr H Me PH

836 i-Pr H Me F

837 i-Pr Me H OH

838 i-Pr Me H F

839 i-Pr H H OH

840 i-Pr H H F

841 i-Pr H Me OH

842 i-Pr H Me F

843 i-Pr Me H OH

844 i-Pr Me H F

845 i-Pr H H OH

846 i-Pr H H F

847 i-Pr H Me OH

848 i-Pr H Me F

849 i-Pr Me H OH

850 i-Pr Me H F

851 i-Pr H H OH

852 i-Pr H H F

853 i-Pr H Me OH

854 i-Pr H Me F

855 i-Pr Me H OH

856 i-Pr Me H F

857 i-Pr H H OH

858 i-Pr H H F

859 i-Pr H Me OH

860 i-Pr H Me F

861 i-Pr Me H OH

862 i-Pr Me H F

863 i-Pr H H OH

864 i-Pr H H F

865 i-Pr Me Me OH

866 i-Pr H Me F

867 i-Pr H Me OH

868 i-Pr Me H F

869 i-Pr H H OH

870 i-Pr H H F

871 i-Pr H Me OH

872 i-Pr H Me F

873 i-Pr Me H OH

874 i-Pr Me H F

875 i-Pr H H OH

876 i-Pr H H F

877 i-Pr H Me OH

878 i-Pr H Me F

879 i-Pr Me H OH

880 i-Pr Me H F

881 Et H H OH

882 Et H H F

883 Et H Me OH

884 Et H Me F

885 Et Me H OH

886 Et Me H F

887 Et H H OH

888 Et H H F

889 Et H Me OH

890 Et H Me F

891 Et Me H OH

892 Et Me H F

893 Et H H OH

894 Et H H F

895 Et H Me OH

896 Et H Me F

897 Et Me H OH

898 Et Me H F

899 Et H H OH

900 Et H H F

901 Et H Me OH

902 Et H Me F

903 Et Me H OH

904 Et Me H F

905 Et H H OH

906 Et H H F

907 Et H Me OH

908 Et H Me F

909 Et Me H OH

910 Et Me H F

911 Et H H OH

912 Et H H F

913 Et H Me OH

914 Et H Me F

915 Et Me H OH

916 Et Me H F

917 Et H H OH

918 Et H H F

919 Et H Me OH

920 Et H Me F

921 Et Me H OH

922 Et Me H F

923 Et H H OH

924 Et H H F

925 Et H Me OH

926 Et H Me F

927 Et Me H OH

928 Et Me H F

929 Et H H OH

930 Et H H F

931 Et H Me OH

932 Et H Me F

933 Et Me H OH

934 Et Me H F

935 Et H H OH

936 Et H H F

937 Et H Me OH

938 Et H Me F

939 Et Me H OH

940 Et Me H F

.


9. A pharmaceutical composition comprising a compound according to claim1, in combination with a pharmaceutically acceptable carrier orexcipient.
 10. A method of treating a viral infection in a subject,comprising administering to the subject a viral inhibitory amount of apharmaceutical composition according to claim
 9. 11. The methodaccording to claim 10, wherein the viral infection is hepatitis C virus.12. A method of inhibiting the replication of hepatitis C virus, themethod comprising contacting the virus with an effective amount of thepharmaceutical composition of claim
 9. 13. The method of claim 10further comprising administering concurrently an additionalanti-hepatitis C virus agent.
 14. The method of claim 11, wherein saidadditional anti-hepatitis C virus agent is selected from the groupconsisting of α-interferon, β-interferon, ribavarin, and adamantine. 15.The method of claim 12, wherein said additional anti-hepatitis C virusagent is an inhibitor of hepatitis C virus helicase, polymerase,metalloprotease, or IRES.
 16. The pharmaceutical composition of claim 9,further comprising another anti-HCV agent.
 17. The pharmaceuticalcomposition of claim 9, further comprising an agent selected frominterferon, ribavirin, amantadine, another HCV protease inhibitor, anHCV polymerase inhibitor, an HCV helicase inhibitor, or an internalribosome entry site inhibitor.
 18. The pharmaceutical composition ofclaim 9, further comprising pegylated interferon.
 19. The pharmaceuticalcomposition of claim 9, further comprising another anti-viral,anti-bacterial, anti-fungal or anti-cancer agent, or an immunemodulator.
 20. The composition of claim 9, further comprising acytochrome P450 monooxygenase inhibitor or a pharmaceutically acceptablesalt thereof.
 21. The composition of claim 20, wherein the cytochromeP450 monooxygenase inhibitor is ritonavir.
 22. A method of treating ahepatitis C viral infection in a subject in need thereof comprisingadministering to the subject therapeutically effective amounts of (a) acytochrome P450 monooxygenase inhibitor or a pharmaceutically acceptablesalt thereof and (b) a compound as set forth in claim 1.